Their use in treating polymorphisms and cancers

Abstract

This disclosure relates to novel crystalline polymorphs of compound 1, as well as processes for their preparation and use. Such polymorphs may be components of pharmaceutical compositions and may be used to treat cancer.

Description

Technical Field

[0001] Cross - reference to related applications

[0001] This application claims priority and the benefit of U.S. Provisional Patent Application No. 63 / 507,954, filed on June 13, 2023, the disclosure of which is incorporated herein by reference in its entirety.

[0002]

[0002] This disclosure relates to novel polymorphic forms of Compound 1 having the structure and chemical name (S)-N-(2-(10-(chloromethyl)-5 - methyl - 4 - oxo - 5,8,9,10 - tetrahydro - 4H - pyrrolo[3’,2’:5,6]naphtho[1,8 - de][1,2]oxazine - 8 - carbonyl)-1H - indol - 5 - yl)-1H - indol - 2 - carboxamide, represented in FIG. 1. This disclosure also targets pharmaceutical compositions containing polymorphic forms of Compound 1 and the therapeutic and / or prophylactic use of such polymorphic forms and compositions. Compound 1 and methods for making it are described in U.S. Patent No. 9,586,974, the disclosure of which is incorporated herein by reference in its entirety.

Background Art

[0003]

[0003] Approximately 610,000 people die from cancer each year in the United States. Worldwide, there are approximately 10 million cancer - related deaths each year, accounting for about one - sixth of all deaths. Despite decades of research in the field of cancer prevention and treatment, the number of cancer - related deaths is increasing year by year, and many cancers either do not respond to traditional chemotherapy and other therapeutic agents or exhibit resistance to them.

Summary of the Invention

Problems to be Solved by the Invention

[0004]

[0004] New compounds for use in the treatment of cancer are still needed.

Means for Solving the Problems

[0005]

[0005] A method for preparing the crystalline form A hydrate of Compound 1 is provided herein.

[0006]

[0006] A method for preparing the crystalline form B DMF solvate of Compound 1 is provided herein.

[0007]

[0007] A method for preparing the crystalline form C anhydride of Compound 1 is provided herein.

[0008] [[ID=1

[13] ]

[0008] A method for preparing the crystalline form E DMSO solvate of Compound 1 is provided herein.

[0009]

[0009] A method for preparing the crystalline form F DMA solvate of Compound 1 is provided herein. [[ID=2

[20] ]

[0010]

[0010] A crystalline form A hydrate of Compound 1 substantially free of crystalline form C anhydride of Compound 1 is provided herein.

[0011] [[ID=2

[26] ]

[0011] A crystalline form C anhydride of Compound 1 substantially free of crystalline form A hydrate of Compound 1 is provided herein.

[0012]

[0012] A crystalline form A hydrate of Compound 1 is provided herein, further characterized in that the crystalline form A hydrate of Compound 1 is converted to the crystalline form C anhydride at a temperature of about 40 °C in anhydrous ethanol over about 2 days.

[0013]

[0013] A crystalline form A hydrate of Compound 1 is provided herein, further characterized in that the crystalline form A hydrate of Compound 1 is converted to the crystalline form C anhydride at a temperature of about 50 °C in anhydrous ethanol over about 1 hour.

[0014]

[0014] A method for producing anhydrous compound 1 crystalline form C is further provided, which includes heating a solution of compound 1 crystalline form A hydrate in anhydrous ethanol at a temperature of about 40°C for about 2 days to obtain anhydrous compound 1 crystalline form C.

[0015]

[0015] In some embodiments, a method for treating cancer in a mammal in need thereof is provided herein, comprising the step of administering an effective amount of any of compound 1 crystalline forms A to F to the mammal.

[0016]

[0016] Compound 1 crystalline form A hydrate is provided herein.

[0017]

[0017] Compound 1, crystalline form B, DMF solvate is provided herein.

[0018]

[0018] Compound 1, in crystalline form C, anhydrous is provided herein.

[0019]

[0019] Compound 1 crystalline form E DMSO solvate is provided herein.

[0020]

[0020] Compound 1 crystalline form F DMA solvate is provided herein.

[0021]

[0021] Compositions comprising a) crystalline form A hydrate of compound 1 or b) crystalline form A hydrate of compound 1 are provided herein.

[0022]

[0022] Compositions comprising a) the crystalline form B DMF solvate of compound 1 or b) the crystalline form B DMF solvate of compound 1 in which it is dissolved are provided herein.

[0023]

[0023] Compositions comprising a) Compound 1 Form C Anhydrous or b) Compound 1 Form C Anhydrous in which it is dissolved are provided herein.

[0024]

[0024] Compositions comprising (a) Compound 1 Form E DMSO solvate or (b) Compound 1 Form E DMSO solvate in which is dissolved are provided herein.

[0025]

[0025] Compositions comprising a) Compound 1 Form F DMA solvate or b) Compound 1 Form F DMA solvate in which it is dissolved are provided herein.

[0026]

[0026] A method for producing Compound 1 Crystal Form C Anhydrous is provided herein, comprising mixing anhydrous ethanol and crystalline form A hydrate to form a slurry, wherein the slurry contains crystalline form C anhydrous. [Brief explanation of the drawing]

[0027] [Figure 1]

[0027] This is a diagram showing the structure of compound 1. [Figure 2]

[0028] This is a powder X-ray diffraction pattern diffractogram of compound 1 crystalline form A hydrate. [Figure 3]

[0029] This graph shows the differential scanning calorimetry curve for compound 1, crystalline form A, hydrate. [Figure 4]

[0030] This graph shows the thermogravimetric analysis curve of Compound 1, crystalline form A, hydrate. [Figure 5]

[0031] This graph shows the dynamic vapor adsorption analysis of compound 1 crystalline form A hydrate. [Figure 6]

[0032] This is the infrared spectrum of compound 1, crystalline form A, hydrate. [Figure 7]

[0033] This is the Raman spectrum of compound 1, crystalline form A, hydrate. [Figure 8]

[0034] This is the 1H nuclear magnetic resonance spectrum of compound 1 crystalline form A hydrate in DMSO-d6. [Figure 9]

[0035] This is a powder X-ray diffraction pattern diffractogram of compound 1, crystalline form B, DMF solvate. [Figure 10]

[0036] This graph shows the differential scanning calorimetry analysis curve of compound 1, crystalline form B, DMF solvate. [Figure 11]

[0037] This graph shows the thermogravimetric analysis curve of Compound 1, crystalline form B, DMF solvate. [Figure 12]

[0038] This is the 1H nuclear magnetic resonance spectrum of compound 1, crystalline form B, DMF solvate in DMSO-d6. [Figure 13]

[0039] This is a powder X-ray diffraction pattern diffractogram of compound 1 (crystal form C, anhydrous). [Figure 14]

[0040] This graph shows the differential scanning calorimetry curve of compound 1, crystalline form C, in its anhydrous state. [Figure 15]

[0041] This graph shows the thermogravimetric analysis curve of compound 1, crystalline form C, in its anhydrous state. [Figure 16]

[0042] This graph shows the dynamic vapor adsorption analysis of compound 1, crystalline form C, in its anhydrous form. [Figure 17]

[0043] This is the infrared spectrum of compound 1, crystalline form C, anhydrous. [Figure 18]

[0044] This is the Raman spectrum of compound 1, crystalline form C, in its anhydrous state. [Figure 19]

[0045] This is the 1H nuclear magnetic resonance spectrum of compound 1, crystalline form C, anhydrous DMSO-d6. [Figure 20]

[0046] This is a powder X-ray diffraction pattern diffractogram of compound 1, crystalline form E, DMSO solvate. [Figure 21]

[0047] This is the DMSO-d6 1H nuclear magnetic resonance spectrum of compound 1, crystalline form E, DMSO solvate. [Figure 22]

[0048] This is a powder X-ray diffraction pattern diffractogram of compound 1, crystalline form F, DMA solvate. [Figure 23]

[0049] This is the 1H nuclear magnetic resonance spectrum of the DMSO-d6 DMA solvate of compound 1 in crystalline form F. [Figures 24A-24C]

[0050] This is an X-ray diffraction pattern diffractogram of compound 1, crystalline form A, hydrate. [Figure 24A] This is an X-ray diffraction pattern diffractogram derived from a 30 mg sample slurry prepared in methanol at 40°C for 2 days. [Figure 24B] This is an X-ray diffraction pattern diffractogram derived from a 30 mg sample obtained by slurring it in methanol and water (approximately 95:5) at 40°C for 2 days and then air-drying it. [Figure 24C] This is an X-ray diffraction pattern diffractogram derived from a 250 mg sample prepared by slurring it in methanol and water (approximately 95:5) at 40°C for 2 days, and then air-drying it. [Figures 25A-25D]

[0051] These are diffractograms of X-ray diffraction patterns of various compounds in their crystalline forms. [Figure 25A] This is a diffractogram of the diffraction pattern of anhydrous C crystal. [Figure 25B] This is a diffractogram of the diffraction pattern of a mixture of crystalline form F DMA solvate and crystalline form A hydrate. [Figure 25C] This is a diffractogram of the diffraction pattern of DMSO solvate in crystalline form E. [Figure 25D] This is a diffraction pattern diffractogram of the crystalline form A hydrate. [Figure 26]

[0052] This graph shows the differential scanning calorimetry curve and TG curve for the Compound 1 crystalline form A hydrate prepared in Example 7. [Figure 27]

[0053] This graph shows the differential scanning calorimetry curve and TG curve for the anhydrous compound 1 crystalline form C prepared in Example 7. [Figure 28A]

[0054] This is the DMSO-d6 1H nuclear magnetic resonance spectrum of compound 1, crystalline form A, hydrate. [Figure 28B] This is the DMSO-d6 1H nuclear magnetic resonance spectrum of compound 1, crystalline form A, hydrate. [Figure 28C] This is the DMSO-d6 1H nuclear magnetic resonance spectrum of compound 1, crystalline form A, hydrate. [Figure 29A]

[0055] This is the 1H nuclear magnetic resonance spectrum of compound 1, crystalline form C, anhydrous DMSO-d6. [Figure 29B] This is the 1H nuclear magnetic resonance spectrum of compound 1, crystalline form C, anhydrous DMSO-d6. [Figure 29C] This is the 1H nuclear magnetic resonance spectrum of compound 1, crystalline form C, anhydrous DMSO-d6. [Modes for carrying out the invention]

[0028]

[0056] Within the scope of this disclosure, it has been found that compound 1 can take on various polymorphic crystalline forms.

[0029]

[0057] The XRPD spectrum shows five observed polymorphs; crystalline form A hydrate is a variable hydrate (approximately 2.6% water content) based on TG analysis, and crystalline form C anhydrous is a non-solvated polymorph.

[0030]

[0058] This disclosure relates to novel crystalline polymorphs of compound 1 and processes for their preparation. Such polymorphs may be components of pharmaceutical compositions and may be used to treat cancer.

[0031]

[0059] In some embodiments, the disclosure provides a compound 1 crystalline form A hydrate. In some embodiments, the crystalline form A hydrate has substantially the X-ray powder diffraction pattern shown in Figure 2.

[0032]

[0060] In some embodiments, the crystalline form A hydrate is further characterized by an X-ray powder diffraction pattern that includes peaks at diffraction angles (2θ) 6.1±0.2°, 8.7±0.2°, 9.7±0.2°, 13.7±0.2°, 13.9±0.2°, 19.4±0.2°, 23.4±0.2°, and 25.4±0.2°, respectively.

[0033]

[0061] In some embodiments, the crystalline form A hydrate is further characterized by an X-ray powder diffraction pattern that includes peaks at diffraction angles (2θ) 6.1±0.2°, 8.7±0.2°, 9.7±0.2°, 13.7±0.2°, and 13.9±0.2°, respectively.

[0034]

[0062] In some embodiments, the crystalline form A hydrate is further characterized by an X-ray powder diffraction pattern that includes peaks at diffraction angles (2θ) 8.7±0.2°, 9.7±0.2°, and 13.9±0.2°, respectively.

[0035]

[0063] In some embodiments, the crystalline form A hydrate has a differential scanning calorimetry (DSC) thermogram (DSC) that includes an endothermic peak at approximately 78.0°C.

[0036]

[0064] In some embodiments, the crystalline form A hydrate has a differential scanning calorimetry thermogram (DSC) that includes a melting transition at approximately 279-281°C.

[0037]

[0065] In some embodiments, the crystalline form A hydrate has substantially the differential scanning calorimetry thermogram (DSC) shown in Figure 3.

[0038]

[0066] In some embodiments, the crystalline form A hydrate has substantially the thermogravimetric analysis (TGA) shown in Figure 4.

[0039]

[0067] In some embodiments, the crystalline form A hydrate is further characterized by an IR spectrum substantially represented in Figure 6.

[0040]

[0068] In some embodiments, the crystalline form A hydrate is 1426±2 cm². ,

[0074] , -1 ,

[0072] , , 1 , -1 , , , -1 ,

[0073] , , , , ,

[0071] , -1 and 1547 ± 2 cm -1 and 1629 ± 2 cm -1 and is further characterized by an IR spectrum having absorption peaks at each of them.

[0041]

[0069] In some embodiments, crystalline form A hydrate is further characterized by a Raman spectrum substantially represented in FIG. 7.

[0042]

[0070] In some embodiments, crystalline form A hydrate is 1407 ± 2 cm -1 , 1443 ± 2 cm -1 , 1540 ± 2 cm -1 , 1578 ± 2 cm -1 and 1628 ± 2 cm -1 and is further characterized by a Raman spectrum having Raman shifts at each of them.

[0043]

[0071] In some embodiments, crystalline form A hydrate is 1407 ± 2 cm -1 , 1540 ± 2 cm -1 and 1578 ± 2 cm -1 and is further characterized by a Raman spectrum having Raman shifts at each of them.

[0044]

[0072] In some embodiments, crystalline form A hydrate is further characterized by a dynamic vapor sorption profile substantially shown in FIG. 5.

[0045]

[0073] In some embodiments, crystalline form A hydrate is a solution in DMSO-d6 substantially shown in FIG. 8 1 and has an 1H NMR spectrum profile.

[0046]

[0074] In some embodiments, the crystalline form A hydrate is found in a solution containing one or more peaks at approximately 3.58 ppm, 4.05 ppm, 4.38 ppm, 4.65 ppm, 4.91 ppm, 7.07 ppm, 7.22 ppm, 7.29 ppm, 7.43 ppm, 7.48 ppm, 7.60 ppm, 7.68 ppm, 7.74 ppm, 7.90 ppm, 8.09 ppm, 8.20 ppm, 8.25 ppm, 10.19 ppm, 11.73 ppm, and 11.84 ppm. 1 It has a 1H NMR spectrum of DMSO-d6.

[0047]

[0075] In some embodiments, the crystalline form A hydrate has a water content of approximately 2.4 wt% of the crystalline form A hydrate as determined by Karl Fischer titration.

[0048]

[0076] In some embodiments, the crystalline form A hydrate is a non-stoichiometric hydrate.

[0049]

[0077] In some embodiments, the present disclosure provides compositions comprising compound 1 crystalline form A hydrate.

[0050]

[0078] In some embodiments, the composition is a composition in which an effective amount of crystalline form A hydrate is dissolved.

[0051]

[0079] In some embodiments, the compositions provided herein include a pharmaceutically acceptable carrier or diluent.

[0052]

[0080] In some embodiments, the composition is substantially free of compound 1 crystalline form C anhydrous.

[0053]

[0081] In some embodiments, the composition is a composition in which crystalline form A hydrate is dissolved, and the amount of dissolved crystalline form A hydrate is at least about 50% by weight of the composition.

[0054]

[0082] In some embodiments, the composition is a composition in which crystalline form A hydrate is dissolved, and the amount of dissolved crystalline form A hydrate is at least about 5% by weight of the composition.

[0055]

[0083] In some embodiments, the composition is a composition in which crystalline form A hydrate is dissolved, and the amount of dissolved crystalline form A hydrate is at least about 1% by weight of the composition.

[0056]

[0084] In some embodiments, the crystalline form A hydrate is a non-stoichiometric hydrate. The disclosure further provides a method for preparing a crystalline form A hydrate in which the hydrate is a non-stoichiometric hydrate. The method for preparing a crystalline form A hydrate comprises mixing compound 1 and methanol:water (v / v) in a ratio of about 95:about 5 to obtain a slurry, and stirring the slurry at about 40°C for about 2 days, wherein the slurry contains the crystalline form A hydrate.

[0057]

[0085] In some embodiments, a method for producing crystalline form A hydrate further includes separating the crystalline form A hydrate from a slurry and drying the separated crystalline form A hydrate.

[0058]

[0086] This disclosure further provides a compound 1 crystalline form B DMF solvate.

[0059]

[0087] In some embodiments, the crystalline form B DMF solvate has substantially the X-ray powder diffraction pattern shown in Figure 9.

[0060]

[0088] In some embodiments, the crystalline form B DMF solvate is further characterized by an X-ray powder diffraction pattern that includes peaks at diffraction angles (2θ) 4.5±0.2°, 7.3±0.2°, 7.7±0.2°, 9.2±0.2°, and 10.3±0.2°, respectively.

[0061]

[0089] In some embodiments, the crystalline form B DMF solvate is further characterized by an X-ray powder diffraction pattern that includes peaks at diffraction angles (2θ) 4.5±0.2°, 7.3±0.2°, and 10.3±0.2°, respectively.

[0062]

[0090] In some embodiments, the crystalline form B DMF solvate has a differential scanning calorimetry (DSC) thermogram (DSC) curve that includes an endothermic peak at approximately 147.0°C.

[0063]

[0091] In some embodiments, the crystalline form B DMF solvate has substantially the differential scanning calorimetry thermogram (DSC) curve shown in Figure 10.

[0064]

[0092] In some embodiments, the crystalline form B DMF solvate has substantially the thermogravimetric analysis (TGA) curve shown in Figure 11.

[0065]

[0093] In some embodiments, the crystalline form B DMF solvate is substantially a solution in DMSO-d6 as shown in Figure 12. 1 It possesses a 1H NMR spectral profile.

[0066]

[0094] In some embodiments, the crystalline form B DMF solvate is in a solution in DMSO-d6 containing one or more peaks at approximately 3.58 ppm, 4.05 ppm, 4.38 ppm, 4.65 ppm, 4.91 ppm, 7.07 ppm, 7.22 ppm, 7.29 ppm, 7.43 ppm, 7.48 ppm, 7.60 ppm, 7.68 ppm, 7.74 ppm, 7.90 ppm, 7.95 ppm, 8.10 ppm, 8.20 ppm, 8.25 ppm, 10.19 ppm, 11.73 ppm, and 11.84 ppm. 1 The 1H NMR spectrum is evaluated.

[0067]

[0095] In some embodiments, crystalline form B is a DMF solvate.

[0068]

[0096] In some embodiments, the disclosure includes compositions comprising a crystalline form B DMF solvate.

[0069]

[0097] In some embodiments, the composition is a composition in which crystalline form B DMF solvate is dissolved.

[0070]

[0098] In some embodiments, the composition comprises a pharmaceutically acceptable carrier or diluent.

[0071]

[0099] In some embodiments, the composition is a composition in which crystalline form B DMF solvate is dissolved, and the dissolved crystalline form B DMF solvate constitutes at least about 50% by weight of the composition.

[0072]

[0100] In some embodiments, the composition is a composition in which crystalline form B DMF solvate is dissolved, and the dissolved crystalline form B DMF solvate is at least about 5% by weight of the composition.

[0073]

[0101] In some embodiments, the composition is a composition in which crystalline form B DMF solvate is dissolved, and the dissolved crystalline form B DMF solvate is at least about 1% by weight of the composition.

[0074]

[0102] This disclosure further provides a method for producing compound 1 crystalline form B DMF solvate, comprising mixing DMF with crystalline form A hydrate to form a solution and stirring the solution to obtain a slurry, wherein the slurry contains crystalline form B DMF solvate.

[0075]

[0103] This disclosure further provides a method for preparing a compound 1 crystalline form B DMF solvate. The crystalline form B DMF solvate may be prepared by mixing form A hydrate and DMF to obtain a solution, and then stirring the solution to obtain a slurry, the slurry containing the crystalline form B DMF solvate.

[0076]

[0104] A method for preparing crystalline form B DMF solvate may further include separating the crystalline form B DMF solvate from the slurry and drying the separated crystalline form B DMF solvate.

[0077]

[0105] This disclosure further provides compound 1 crystalline form C anhydrous.

[0078]

[0106] In some embodiments, the crystalline form C anhydrous has substantially the X-ray powder diffraction pattern shown in Figure 13.

[0079]

[0107] In some embodiments, the anhydrous crystalline form C is further characterized by an X-ray powder diffraction pattern that includes peaks at diffraction angles (2θ) 9.8±0.2°, 11.7±0.2°, 12.0±0.2°, 13.4±0.2°, and 15.2±0.2°, respectively.

[0080]

[0108] In some embodiments, the anhydrous crystalline form C is further characterized by an X-ray powder diffraction pattern that includes peaks at diffraction angles (2θ) 9.8±0.2°, 11.7±0.2°, and 15.2±0.2°, respectively.

[0081]

[0109] In some embodiments, the crystalline form of C anhydrous has substantially the differential scanning calorimetry thermogram (DSC) curve shown in Figure 14.

[0082]

[0110] In some embodiments, the crystalline form of C anhydrous has a differential scanning calorimetry (DSC) thermogram (DSC) curve that includes an endothermic peak at approximately 100.55°C. In some embodiments, the crystalline form of C anhydrous has a thermogravimetric analysis (TGA) curve substantially as shown in Figure 15.

[0083]

[0111] In some embodiments, the crystalline form of C anhydrous is further characterized by an IR spectrum substantially represented in Figure 17.

[0084]

[0112] In some embodiments, the crystalline form of C anhydrous is 1402±2cm². -1 , 1421±2cm-1 , 1539±2cm -1 , and 1616±2cm -1 The IR spectrum is further characterized by having an absorption peak in each of the following regions.

[0085]

[0113] In some embodiments, the crystalline form of C anhydrous is further characterized by a Raman spectrum substantially represented in Figure 18.

[0086]

[0114] In some embodiments, the crystalline form of C anhydrous is 1399±2cm². -1 , 1584±2cm -1 , and 1623±2cm -1 The Raman spectrum is further characterized by each having a Raman shift.

[0087]

[0115] In some embodiments, the crystalline form C anhydrous further features a dynamic vapor adsorption profile substantially as shown in Figure 16.

[0088]

[0116] In some embodiments, the crystalline form C anhydrous is substantially a solution in DMSO-d6 as shown in Figure 19. 1 It possesses a 1H NMR spectral profile.

[0089]

[0117] In some embodiments, the anhydrous crystalline form of C is a solution containing one or more peaks at approximately 3.58 ppm, 4.05 ppm, 4.38 ppm, 4.65 ppm, 4.91 ppm, 7.07 ppm, 7.22 ppm, 7.29 ppm, 7.43 ppm, 7.49 ppm, 7.60 ppm, 7.68 ppm, 7.74 ppm, 7.90 ppm, 8.09 ppm, 8.20 ppm, 8.25 ppm, 10.19 ppm, 11.73 ppm, and 11.84 ppm. 1 It has a 1H NMR spectrum of DMSO-d6.

[0090]

[0118] In some embodiments, the present disclosure provides compositions comprising compound 1 crystalline form C anhydride.

[0091]

[0119] In some embodiments, the composition is a composition in which crystalline form C anhydride is dissolved.

[0092]

[0120] In some embodiments, the composition comprises a pharmaceutically acceptable carrier or diluent.

[0093]

[0121] In some embodiments, the composition is substantially free of compound 1 crystalline form A hydrate.

[0094]

[0122] In some embodiments, the composition is a composition in which crystalline form C anhydrous is dissolved, and the dissolved crystalline form C anhydrous is at least about 50% by weight of the composition.

[0095]

[0123] In some embodiments, the composition is a composition in which crystalline form C anhydrous is dissolved, and the dissolved crystalline form C anhydrous is at least about 5% by weight of the composition.

[0096]

[0124] In some embodiments, the composition is a composition in which crystalline form C anhydrous is dissolved, and the dissolved crystalline form C anhydrous is at least about 1% by weight of the composition.

[0097]

[0125] This disclosure further provides a method for preparing anhydrous compound 1 in crystalline form C. Anhydrous compound 1 in crystalline form C may be prepared by mixing hydrated compound 1 in crystalline form A with acetonitrile or ethanol to obtain a slurry, and then stirring the slurry, wherein the slurry contains anhydrous compound 1 in crystalline form C.

[0098]

[0126] This disclosure further provides a method for producing compound 1 crystalline form C anhydrous, comprising mixing acetonitrile and crystalline form A hydrate to form a slurry, and stirring the solution at about 40°C for about one week, wherein the slurry contains crystalline form C anhydrous.

[0099]

[0127] In some embodiments, the method for producing crystalline anhydrous C further includes separating the crystalline anhydrous C from a slurry and drying the separated crystalline anhydrous C.

[0100]

[0128] This disclosure further provides a method for producing Compound 1 Crystalline Form C Anhydrous, comprising mixing anhydrous ethanol and crystalline form A hydrate to form a slurry, and stirring the slurry at approximately 40°C for approximately 2 days, wherein the slurry contains crystalline form C anhydrous.

[0101]

[0129] This disclosure further provides a method for producing Compound 1 Crystalline Form C Anhydrous, comprising mixing anhydrous ethanol and crystalline form A hydrate to form a slurry, and stirring the slurry at about 50°C for about 1 hour, wherein the slurry contains crystalline form C anhydrous.

[0102]

[0130] In some embodiments, the method for producing crystalline anhydrous C further includes separating the crystalline anhydrous C from a slurry and drying the separated crystalline anhydrous C.

[0103]

[0131] This disclosure further provides a compound 1 crystalline form E DMSO solvate.

[0104]

[0132] In some embodiments, the crystalline form E DMSO solvate has substantially the X-ray powder diffraction pattern shown in Figure 20.

[0105]

[0133] In some embodiments, the crystalline form E DMSO solvate is further characterized by an X-ray powder diffraction pattern containing peaks at diffraction angles (2θ) 6.0±0.2°, 6.5±0.2°, 8.6±0.2°, 9.1±0.2°, and 11.9±0.2°, respectively.

[0106]

[0134] In some embodiments, the crystalline form E DMSO solvate is further characterized by an X-ray powder diffraction pattern that includes peaks at diffraction angles (2θ) 6.0±0.2°, 6.5±0.2°, and 8.6±0.2°, respectively.

[0107]

[0135] In some embodiments, the crystalline form E DMSO solvate is substantially a solution in DMSO-d6 as shown in Figure 21. 1 It possesses a 1H NMR spectral profile.

[0108]

[0136] In some embodiments, the crystalline form E in DMSO-d6 solution contains one or more peaks at approximately 2.53 ppm, 3.58 ppm, 4.05 ppm, 4.38 ppm, 4.65 ppm, 4.91 ppm, 7.07 ppm, 7.22 ppm, 7.29 ppm, 7.43 ppm, 7.48 ppm, 7.60 ppm, 7.68 ppm, 7.74 ppm, 7.90 ppm, 8.09 ppm, 8.20 ppm, 8.25 ppm, 10.19 ppm, 11.73 ppm, and 11.84 ppm. 1 The 1H NMR spectrum is evaluated.

[0109]

[0137] In some embodiments, the crystalline form E is a DMSO solvate.

[0110]

[0138] This disclosure further provides a method for preparing a crystalline form E DMSO solvate of compound 1. The crystalline form E DMSO solvate may be prepared by mixing crystalline form A hydrate and DMSO to obtain a solution, then adding water dropwise to the solution to obtain a slurry, and stirring the slurry, wherein the slurry contains the crystalline form E DMSO solvate.

[0111]

[0139] This disclosure further provides a method for producing compound 1 crystalline form E DMSO solvate, comprising mixing DMSO and crystalline form A hydrate to form a solution, adding water dropwise to the solution to form a slurry, and stirring the slurry for about one day, wherein the slurry contains crystalline form E DMSO solvate.

[0112]

[0140] In some embodiments, the method further includes separating the crystalline form E DMSO solvate from the slurry and drying the separated crystalline form E DMSO solvate.

[0113]

[0141] In some embodiments, the present disclosure provides compositions comprising a crystalline form E DMSO solvate.

[0114]

[0142] In some embodiments, the composition is a composition in which crystalline form E DMSO solvate is dissolved.

[0115]

[0143] In some embodiments, the composition comprises a pharmaceutically acceptable carrier or diluent.

[0116]

[0144] In some embodiments, the composition is a composition in which crystalline form E DMSO solvate is dissolved, and the dissolved crystalline form E DMSO solvate is at least about 50% by weight of the composition.

[0117]

[0145] In some embodiments, the composition is a composition in which crystalline form E DMSO solvate is dissolved, and the dissolved crystalline form E DMSO solvate is at least about 5% by weight of the composition.

[0118]

[0146] In some embodiments, the composition is a composition in which crystalline form E DMSO solvate is dissolved, and the dissolved crystalline form E DMSO solvate is at least about 1% by weight of the composition.

[0119]

[0147] This disclosure further provides a compound 1 crystalline form F DMA solvate.

[0120]

[0148] In some embodiments, the crystalline form of FDMA solvate has substantially the X-ray powder diffraction pattern shown in Figure 22.

[0121]

[0149] In some embodiments, the crystalline form of F DMA solvate is further characterized by an X-ray powder diffraction pattern that includes peaks at diffraction angles (2θ) 7.8±0.2°, 8.1±0.2°, 9.1±0.2°, 9.5±0.2°, and 9.9±0.2°, respectively.

[0122]

[0150] In some embodiments, the crystalline form of F DMA solvate is further characterized by an X-ray powder diffraction pattern that includes peaks at diffraction angles (2θ) 8.1±0.2°, 9.1±0.2°, and 9.9±0.2°, respectively.

[0123]

[0151] In some embodiments, the crystalline form F DMA solvate is substantially a solution in DMSO-d6 as shown in Figure 23. 1 This is the 1H NMR spectral profile.

[0124]

[0152] In some embodiments, the crystalline form of F DMA solvate in solution in DMSO-d6 contains one or more peaks at approximately 1.95 ppm, 2.78 ppm, 2.94 ppm, 3.58 ppm, 4.05 ppm, 4.38 ppm, 4.65 ppm, 4.91 ppm, 7.07 ppm, 7.22 ppm, 7.29 ppm, 7.43 ppm, 7.48 ppm, 7.60 ppm, 7.68 ppm, 7.74 ppm, 7.90 ppm, 8.09 ppm, 8.20 ppm, 8.25 ppm, 10.19 ppm, 11.73 ppm, and 11.84 ppm. 1 This is an H NMR spectrum.

[0125]

[0153] In some embodiments, the crystalline form F DMA solvate is a mono-DMA solvate.

[0126]

[0154] This disclosure further provides compositions comprising a crystalline form F DMA solvate.

[0127]

[0155] In some embodiments, the composition is a composition in which a crystalline form FDMA solvate is dissolved.

[0128]

[0156] This disclosure further provides a method for treating cancer in a mammal in need thereof, comprising the step of administering an effective amount of one of the crystalline forms A to F of compound 1 to the mammal. In some embodiments, the method comprises administering a composition in which one of the forms A to F is dissolved to the mammal.

[0129]

[0157] In some embodiments, the composition comprises a pharmaceutically acceptable carrier or diluent.

[0130]

[0158] In some embodiments, the composition is a composition in which crystalline F DMA solvate is dissolved, and the dissolved crystalline F DMA solvate constitutes at least about 50% by weight of the composition.

[0131]

[0159] In some embodiments, the composition is a composition in which crystalline F DMA solvate is dissolved, and the dissolved crystalline F DMA solvate is at least about 5% by weight of the composition.

[0132]

[0160] In some embodiments, the composition is a composition in which crystalline form F DMA solvate is dissolved, and the dissolved crystalline form F DMA solvate is at least about 1% by weight of crystals relative to the weight of the composition.

[0133]

[0161] This disclosure further provides a method for preparing a crystalline form F DMA solvate of compound 1. The crystalline form F DMA solvate may be prepared by (i) mixing a mixture of crystalline form A hydrate and form C anhydrous, and (ii) mixing DMA and H2O to obtain a slurry, and stirring the slurry, wherein the slurry contains the crystalline form F DMA solvate.

[0134]

[0162] The disclosure further provides a method for producing compound 1 crystalline form F DMA solvate, comprising mixing a mixture of DMA:H2O in a ratio of about 70:about 30 with crystalline form A hydrate and crystalline form C anhydrous to form a slurry, and stirring the slurry for about one week, wherein the slurry contains crystalline form F DMA solvate.

[0135]

[0163] In some embodiments, the DMA is “dry” DMA. As used herein, “dry” means that the DMA contains about 0.01% or less of water relative to the weight of the DMA.

[0136]

[0164] In some embodiments, the method for preparing a crystalline F DMA solvate further includes separating the crystalline F DMA solvate from a slurry and drying the separated crystalline F DMA solvate.

[0137]

[0165] This disclosure further provides a nonstoichiometric hydrate of compound 1 in crystalline form A, characterized in that compound 1 in crystalline form A hydrate is converted to crystalline form C anhydrous in anhydrous ethanol at a temperature of 50°C for about 1 hour.

[0138]

[0166] A method for producing anhydrous compound 1 crystalline form C is further provided, which includes heating a solution of compound 1 crystalline form A hydrate in anhydrous ethanol at a temperature of about 50°C for about 1 hour to obtain anhydrous compound 1 crystalline form C.

[0139]

[0167] This disclosure further provides a nonstoichiometric hydrate of compound 1 in crystalline form A, characterized in that compound 1 in crystalline form A hydrate is converted to crystalline form C anhydrous in anhydrous ethanol at a temperature of about 40°C for about 2 days.

[0140]

[0168] A method for producing anhydrous compound 1 crystalline form C is further provided, which includes heating a solution of compound 1 crystalline form A hydrate in anhydrous ethanol at a temperature of about 40°C for about 2 days to obtain anhydrous compound 1 crystalline form C.

[0141]

[0169] A method for producing anhydrous compound 1 crystalline form C is further provided, which includes heating a solution of compound 1 crystalline form A hydrate in anhydrous ethanol at a temperature of about 40°C for about 2 days to obtain anhydrous compound 1 crystalline form C.

[0142]

[0170] This disclosure further provides a hydrate of compound 1 crystalline form A that is substantially free of compound 1 crystalline form C anhydride.

[0143]

[0171] This disclosure further provides Compound 1 Crystal Form C, an anhydrous form of Compound 1 that substantially does not contain Compound 1 Crystal Form A hydrate.

[0144]

[0172] The present disclosure further provides a method for treating cancer in a mammal in need thereof, comprising the step of administering an effective amount of compound 1 in crystalline form to the mammal, wherein the crystalline form is crystalline form A hydrate, crystalline form B DMF solvate, crystalline form C anhydrous, crystalline form E DMSO solvate, crystalline form F DMA solvate, or a mixture thereof.

[0145]

[0173] The present disclosure further provides a method for treating cancer in a mammal in need, comprising the step of administering to the mammal an effective amount of a composition in which compound 1 crystalline form A hydrate, compound 1 crystalline form B DMF solvate, compound 1 crystalline form C anhydrous, compound 1 crystalline form E DMSO solvate, or compound 1 crystalline form F DMA solvate, or a mixture thereof is dissolved.

[0146]

[0174] Some embodiments involve administering an effective amount of Compound 1 Crystalline Form A hydrate or an effective amount of a composition in which Compound 1 Crystalline Form A hydrate is dissolved.

[0147]

[0175] In some embodiments, crystalline form A hydrate is a variable hydrate between hemihydrate and monohydrate. In some embodiments, crystalline form A is a hydrate containing 0.5 to 0.8 molar equivalents of water per molar equivalent of crystalline form A. In some embodiments, crystalline form A hydrate is a non-stoichiometric hydrate.

[0148]

[0176] Some embodiments involve administering an effective amount of Compound 1 Crystallized Form A hydrate or an effective amount of a composition in which Compound 1 Crystallized Form A hydrate is dissolved, wherein Compound 1 Crystallized Form A hydrate has substantially the X-ray powder diffraction pattern shown in Figure 2. In some embodiments, the Crystallized Form A hydrate is further characterized by an X-ray powder diagram having characteristic reflections at the following d values: 14.4886 Å, 10.1636 Å, 9.1368 Å, 6.4541 Å, and 6.3709 Å.

[0149]

[0177] In some embodiments, the crystalline form A hydrate is further characterized by an X-ray powder diffraction pattern that may include peaks at diffraction angles (2θ): 6.1±0.2°, 8.7±0.2°, 9.7±0.2°, 13.7±0.2°, 13.9±0.2°, 19.4±0.2°, 23.4±0.2°, and 25.4±0.2°, respectively.

[0150]

[0178] In some embodiments, the crystalline form A hydrate is further characterized by an X-ray powder diffraction pattern that may include peaks at diffraction angles (2θ): 6.1±0.2°, 8.7±0.2°, 9.7±0.2°, 13.7±0.2°, and 13.9±0.2°, respectively.

[0151]

[0179] In some embodiments, the crystalline form A hydrate is further characterized by an X-ray powder diffraction pattern that may include peaks at diffraction angles (2θ): 8.7±0.2°, 9.7±0.2°, and 13.9±0.2°, respectively.

[0152]

[0180] Some embodiments involve administering an effective amount of a composition in which an effective amount of crystalline form A hydrate or compound 1 crystalline form A hydrate is dissolved, wherein the compound 1 crystalline form A hydrate has a differential scanning calorimetry (DSC) thermogram (DSC) which may include an endothermic peak at about 78.0°C and a melting transition at about 279–281°C. Some embodiments are further characterized in that the crystalline form A hydrate has a differential scanning calorimetry (DSC) substantially shown in Figure 3. Some embodiments are further characterized in that the crystalline form A hydrate has a thermogravimetric analysis (TGA) substantially shown in Figure 4.

[0153]

[0181] Some embodiments involve administering an effective amount of Compound 1 in crystalline form A hydrate or an effective amount of a composition in which Compound 1 in crystalline form A hydrate is dissolved, wherein the amount of Compound 1 in crystalline form A hydrate is 1426 ± 2 cm³. -1 , 1547±2cm -1 , and 1629±2cm -1 Each of them has an IR spectrum with an absorption peak.

[0154]

[0182] Some embodiments are 1407±2cm -1 , 1443±2cm -1 , 1540±2cm-1, 1578±2cm -1 , and 1628±2cm -1 The method comprises administering an effective amount of compound 1 crystalline form A hydrate, characterized by a Raman spectrum having a Raman shift, to each of the following:

[0155]

[0183] Some embodiments involve administering an effective amount of Compound 1 Crystalline A hydrate or an effective amount of a composition in which Compound 1 Crystalline A hydrate is dissolved, wherein the Compound 1 Crystalline A hydrate is dissolved in DMSO-d6 with one or more peaks at approximately 3.58 ppm, 4.05 ppm, 4.38 ppm, 4.65 ppm, 4.91 ppm, 7.07 ppm, 7.22 ppm, 7.29 ppm, 7.43 ppm, 7.48 ppm, 7.60 ppm, 7.68 ppm, 7.74 ppm, 7.90 ppm, 8.09 ppm, 8.20 ppm, 8.25 ppm, 10.19 ppm, 11.73 ppm, and 11.84 ppm. 1 The 1H NMR spectrum is evaluated.

[0156]

[0184] Some embodiments involve administering an effective amount of Compound 1 in crystalline form A hydrate or an effective amount of a composition in which Compound 1 in crystalline form A hydrate is dissolved, wherein the Compound 1 in crystalline form A hydrate has a water content of about 2.4 wt% of the crystalline form A hydrate as determined by Karl Fischer titration.

[0157]

[0185] Some embodiments involve administering an effective amount of a composition containing crystalline form A hydrate or an effective amount of a composition in which compound 1 crystalline form A hydrate is dissolved. The composition may contain at least one pharmaceutically acceptable carrier or diluent.

[0158]

[0186] Some embodiments involve administering an effective amount of the composition in which Compound 1 Form A hydrate is dissolved, the dissolved Compound 1 Form A hydrate being about 0.1 to 75% by weight (inclusive) of the composition, including embodiments in which the dissolved Compound 1 Form A hydrate is, for example, about 1% by weight of the composition or 5% by weight of the composition in crystal form.

[0159]

[0187] In some embodiments, a method for preparing crystalline form A hydrate of compound 1 is provided herein. The hydrate (which may be a non-stoichiometric hydrate) may be formed by mixing methanol, water, and compound 1 to form a slurry, and then stirring the slurry, wherein the slurry contains crystalline form A hydrate.

[0160]

[0188] This disclosure further provides a method for producing a nonstoichiometric hydrate of compound 1 in crystalline form A, comprising mixing methanol:water (v / v) in a ratio of about 95:about 5 with compound 1 to form a slurry, and stirring the slurry at about 40°C for about 2 days, wherein the slurry contains crystalline form A hydrate. In some embodiments, the crystalline form A hydrate is separated from the slurry and dried or dried to obtain crystalline form A hydrate.

[0161]

[0189] Some embodiments involve administering an effective amount of crystalline form A hydrate substantially free of crystalline form C anhydrous of compound 1, or an effective amount of a composition in which crystalline form A hydrate substantially free of crystalline form C anhydrous is dissolved. The crystalline form C anhydrous of compound 1 is described below.

[0162]

[0190] In some embodiments, the composition contains less than 4% (w / w) of anhydrous crystalline form C. In some embodiments, the composition contains hydrated crystalline form A that is substantially free of anhydrous crystalline form C, and the composition contains less than 2% (w / w) of anhydrous crystalline form C.

[0163]

[0191] This disclosure further provides a method for preparing a composition comprising a hydrate of compound 1 in crystalline form A that is substantially free of compound 1 in crystalline form C anhydrous.

[0164]

[0192] In some embodiments, the nonstoichiometric hydrate of compound 1 in crystalline form A is further characterized by being converted to compound 1 in crystalline form C anhydrous in anhydrous ethanol at a temperature of 50°C for about 1 hour.

[0165]

[0193] In some embodiments, the nonstoichiometric hydrate of compound 1 in crystalline form A is further characterized by being converted to compound 1 in crystalline form C anhydrous in anhydrous ethanol at a temperature of about 40°C for about 2 days.

[0166]

[0194] A method for producing anhydrous compound 1 crystalline form C is further provided, which includes heating a solution of compound 1 crystalline form A hydrate, which is a non-stoichiometric hydrate, in anhydrous ethanol at a temperature of about 40°C for about 2 days to obtain anhydrous compound 1 crystalline form C.

[0167]

[0195] Some embodiments include compound 1 crystalline form B of the DMF solvate.

[0168]

[0196] Some embodiments include a compound 1 crystalline form B DMF solvate having substantially the X-ray powder diffraction pattern shown in Figure 9. The compound 1 crystalline form B DMF solvate is further characterized by an X-ray powder diagram having characteristic reflections at the following d values: 19.8119 Å, 12.1760 Å, 11.4515 Å, 9.5708 Å, and 8.5881 Å.

[0169]

[0197] In some embodiments, the compound 1 crystalline form B DMF solvate is characterized by an X-ray powder diffraction pattern that may contain peaks at diffraction angles (2θ): 4.5±0.2°, 7.3±0.2°, 7.7±0.2°, 9.2±0.2°, and 10.3±0.2°, respectively.

[0170]

[0198] In some embodiments, the crystalline form B DMF solvate has a differential scanning calorimetry thermogram (DSC) that may include an endothermic peak at approximately 147.0°C, as shown in Figure 10.

[0171]

[0199] In some embodiments, the compound 1 crystalline form B DMF solvate is further characterized by having substantially the differential scanning calorimetry thermogram (DSC) shown in Figure 10.

[0172]

[0200] In some embodiments, the compound 1 crystalline form B DMF solvate is further characterized by having substantially the thermogravimetric analysis (TGA) shown in Figure 11.

[0173]

[0201] In some embodiments, the compound 1 crystalline form B DMF solvate is characterized by a 18.3% weight loss from the start up to 185°C, as shown in Figure 11, as determined by TGA analysis.

[0174]

[0202] Some embodiments describe a solution in DMSO-d6 containing one or more peaks at approximately 3.58 ppm, 4.05 ppm, 4.38 ppm, 4.65 ppm, 4.91 ppm, 7.07 ppm, 7.22 ppm, 7.29 ppm, 7.43 ppm, 7.48 ppm, 7.60 ppm, 7.68 ppm, 7.74 ppm, 7.90 ppm, 7.95 ppm, 8.10 ppm, 8.20 ppm, 8.25 ppm, 10.19 ppm, 11.73 ppm, and 11.84 ppm. 1 The compound 1 having a 1H NMR spectrum contains a DMF solvate in crystalline form B. In some embodiments, crystalline form B is a DMF solvate.

[0175]

[0203] Some embodiments include a method for preparing crystalline form B as a DMF solvate of compound 1. The method for preparing crystalline form B DMF solvate includes mixing DMF and crystalline form A hydrate to form a solution, and stirring the solution to obtain a slurry, the slurry containing crystalline form B DMF solvate. An additional embodiment of the method is to separate the crystalline form B DMF solvate from the slurry and dry or evaporate it to form crystalline form B DMF solvate.

[0176]

[0204] Some embodiments include one or more of the following features: a composition in which the composition is about 1 to 75% by weight (including both ends) of crystalline form B DMF solvate, including embodiments in which the composition is, for example, about 1% by weight of crystalline form B DMF solvate and about 5% by weight of crystalline form B DMF solvate. The composition may include at least one pharmaceutically acceptable carrier or diluent.

[0177]

[0205] Some embodiments include compound 1 in crystalline form C.

[0178]

[0206] Some embodiments include compound 1 crystalline form C anhydrous having substantially the X-ray powder diffraction pattern shown in Figure 13.

[0179]

[0207] In some embodiments, the anhydrous compound 1 crystalline form C is further characterized by an X-ray powder diagram having characteristic reflections at the following d values: 9.0620 Å, 7.5893 Å, 7.3873 Å, 6.6075 Å, and 5.8212 Å.

[0180]

[0208] In some embodiments, the anhydrous compound 1 crystalline form C is further characterized by an X-ray powder diagram having characteristic reflections at the following d values: 9.0620 Å, 7.5893 Å, and 5.8212 Å.

[0181]

[0209] In some embodiments, the anhydrous compound 1 crystalline form C is characterized by an X-ray powder diffraction pattern that may include peaks at diffraction angles (2θ): 9.8±0.2°, 11.7±0.2°, 12.0±0.2°, 13.4±0.2°, and 15.2±0.2°, respectively.

[0182]

[0210] In some embodiments, the anhydrous compound 1 crystalline form C is characterized by an X-ray powder diffraction pattern that may include peaks at diffraction angles (2θ): 9.8±0.2°, 11.7±0.2°, and 15.2±0.2°, respectively.

[0183]

[0211] In some embodiments, the compound 1 crystalline form C anhydrous is further characterized by having substantially the differential scanning calorimetry thermogram (DSC) shown in Figure 14.

[0184]

[0212] In some embodiments, the anhydrous compound 1 crystalline form C is also characterized by having a differential scanning calorimetry thermogram (DSC) that may include an endothermic peak at approximately 100.55°C.

[0185]

[0213] Some embodiments include compound 1 crystalline form C anhydride having substantially the thermogravimetric analysis (TGA) shown in Figure 15. In some embodiments, the crystalline form C anhydride is characterized by a weight loss of approximately 0.4% from the start to about 135°C, as shown in Figure 15, as determined by TGA analysis.

[0186]

[0214] In some embodiments, compound 1 crystalline form C anhydrous also features a dynamic vapor adsorption profile substantially shown in Figure 16.

[0187]

[0215] In some embodiments, the crystalline form C anhydride of compound 1 is also characterized by an IR spectrum substantially shown in Figure 17. In some embodiments, the crystalline form C anhydride is 1402±2 cm⁻¹. -1 , 1421±2cm -1 , 1539±2cm -1 , and 1616±2cm -1The IR spectrum is further characterized by having absorption peaks in each of the following embodiments. In some embodiments, the crystalline form of C anhydride is also characterized by a Raman spectrum substantially shown in Figure 18. In some embodiments, the crystalline form of C anhydride is 1399 ± 2 cm⁻¹ -1 , 1584±2cm -1 , and 1623±2cm -1 The Raman spectrum is further characterized by each having a Raman shift.

[0188]

[0216] Some embodiments describe a solution in DMSO-d6 containing one or more peaks at approximately 3.58 ppm, 4.05 ppm, 4.38 ppm, 4.65 ppm, 4.91 ppm, 7.07 ppm, 7.22 ppm, 7.29 ppm, 7.43 ppm, 7.49 ppm, 7.60 ppm, 7.68 ppm, 7.74 ppm, 7.90 ppm, 8.09 ppm, 8.20 ppm, 8.25 ppm, 10.19 ppm, 11.73 ppm, and 11.84 ppm. 1 Compound 1 having an H NMR spectrum contains an anhydrous form of C.

[0189]

[0217] Some embodiments include a method for preparing crystalline form C anhydride as the anhydride of compound 1. The method for preparing crystalline form C anhydride includes mixing acetonitrile and crystalline form A hydrate to form a slurry. The method also includes stirring the solution at about 40°C for about one week to obtain the slurry. The method includes the slurry containing crystalline form C anhydride. Some embodiments of the method include separating crystalline form C anhydride from the slurry and drying or freezing it to form crystalline form C anhydride.

[0190]

[0218] Some embodiments include compositions containing anhydrous crystalline form C substantially free of crystalline form A hydrate, and compositions containing anhydrous crystalline form C substantially free of crystalline form A hydrate. In some embodiments, the composition contains less than 4% (w / w) of crystalline form A hydrate. Some embodiments include compositions containing anhydrous crystalline form C substantially free of crystalline form A hydrate, and the composition contains less than 2% (w / w) of crystalline form A hydrate. Some embodiments include preparing compositions containing anhydrous crystalline form C, which is an anhydrous, substantially free of crystalline form A hydrate, which is a hydrate.

[0191]

[0219] Some embodiments include a method for preparing anhydrous compound 1 in crystalline form C. The method for preparing anhydrous compound 1 in crystalline form C also includes mixing anhydrous ethanol and compound 1 in crystalline form A hydrate to form a slurry. The method includes stirring the slurry at about 40°C for about 2 days. The method includes the slurry containing anhydrous compound 1 in crystalline form C. Some embodiments of the method include separating the anhydrous compound 1 in crystalline form C from the slurry and drying or freezing it to form anhydrous compound 1 in crystalline form C.

[0192]

[0220] In some embodiments, a method for producing an anhydrous compound 1 crystalline form C is provided herein, wherein the anhydrous compound 1 crystalline form C substantially does not contain compound 1 crystalline form A hydrate.

[0193]

[0221] Some embodiments include compositions of crystalline form C anhydrous in which the composition is at least about 1 to 75% by weight (including both ends) of crystalline form C anhydrous, for example, in embodiments in which the composition is about 1% by weight of crystalline form C anhydrous or about 5% by weight of crystalline form C anhydrous. The composition may contain at least one pharmaceutically acceptable carrier or diluent.

[0194]

[0222] Some embodiments include a method for preparing anhydrous compound 1 in crystalline form C. The method for preparing anhydrous compound 1 in crystalline form C includes mixing anhydrous ethanol and hydrated compound A in crystalline form to form a slurry. The method includes stirring the slurry at about 50°C for about 1 hour. The method also includes the slurry containing anhydrous compound 1 in crystalline form C. Some embodiments of the method include separating the anhydrous compound 1 in crystalline form C from the slurry and drying or freezing it to form anhydrous compound 1 in crystalline form C.

[0195]

[0223] Some embodiments include compound 1 crystalline form E DMSO solvate.

[0196]

[0224] Some embodiments include a crystalline form E DMSO solvate having substantially the X-ray powder diffraction pattern shown in Figure 20.

[0197]

[0225] In some embodiments, the crystalline E DMSO solvate is characterized by an X-ray powder diagram having characteristic reflections at the following d values: 14.7791 Å, 13.6398 Å, 10.2578 Å, 9.7391 Å, and 7.4243 Å. In some embodiments, the crystalline E DMSO solvate is further characterized by an X-ray powder diffraction pattern that may contain peaks at diffraction angles (2θ): 6.0±0.2°, 6.5±0.2°, 8.6±0.2°, 9.1±0.2°, and 11.9±0.2°. In some embodiments, the crystalline E DMSO solvate is further characterized by an X-ray powder diffraction pattern that may contain peaks at diffraction angles (2θ): 6.0±0.2°, 6.5±0.2°, and 8.6±0.2°.

[0198]

[0226] In some embodiments, the crystalline form E DMSO solvate in DMSO-d6 solution may contain one or more peaks at approximately 2.53 ppm, 3.58 ppm, 4.05 ppm, 4.38 ppm, 4.65 ppm, 4.91 ppm, 7.07 ppm, 7.22 ppm, 7.29 ppm, 7.43 ppm, 7.48 ppm, 7.60 ppm, 7.68 ppm, 7.74 ppm, 7.90 ppm, 8.09 ppm, 8.20 ppm, 8.25 ppm, 10.19 ppm, 11.73 ppm, and 11.84 ppm. 1 It is characterized by having an H NMR spectrum.

[0199]

[0227] Some embodiments include a method for preparing a crystalline form E DMSO solvate of compound 1. The method for preparing a crystalline form E DMSO solvate includes mixing DMSO and crystalline form A hydrate to form a solution. The method includes adding water dropwise to form a slurry and stirring the slurry for about one day. The method includes the slurry containing a crystalline form E DMSO solvate. Some embodiments of the method include separating the crystalline form E DMSO solvate from the slurry and drying or freezing it to form a crystalline form E DMSO solvate.

[0200]

[0228] Some embodiments may include one or more of the following features: a composition in which the composition is about 1 to 75% by weight (including both ends) of crystalline form E DMSO solvate, for example, an embodiment in which the composition is about 1% by weight of crystalline form E DMSO solvate or about 5% by weight of crystalline form E DMSO solvate. The composition may include at least about one pharmaceutically acceptable carrier or diluent.

[0201]

[0229] Some embodiments include the crystalline form F DMA solvate of compound 1.

[0202]

[0230] Some embodiments include a crystalline form of FDMA solvate having substantially the X-ray powder diffraction pattern shown in Figure 22.

[0203]

[0231] In some embodiments, the crystalline form F DMA solvate is characterized by an X-ray powder diagram having characteristic reflections at the following d values: 11.3925 Å, 10.9421 Å, 9.7391 Å, 9.3487 Å, and 8.9342 Å.

[0204]

[0232] In some embodiments, the crystalline form of F DMA solvate is further characterized by an X-ray powder diffraction pattern that may include peaks at diffraction angles (2θ): 7.8±0.2°, 8.1±0.2°, 9.1±0.2°, 9.5±0.2°, and 9.9±0.2°, respectively.

[0205]

[0233] In some embodiments, the crystalline form of F DMA solvate is further characterized by an X-ray powder diffraction pattern that may include peaks at diffraction angles (2θ): 8.1±0.2°, 9.1±0.2°, and 9.9±0.2°, respectively.

[0206]

[0234] Some embodiments include a method for preparing crystalline form F as a DMA solvate of compound 1. The method for preparing crystalline form F DMA solvate includes mixing a mixture of about 70:about 30 DMA:H2O and crystalline form A hydrate and crystalline form C anhydrous to form a slurry, stirring the slurry for about one week, so that the slurry contains crystalline form F DMA solvate, and drying or freezing the slurry to form crystalline form F DMA solvate. In some embodiments, DMA is dry DMA.

[0207]

[0235] In some embodiments, the crystalline form F DMA solvate may contain one or more peaks at approximately 1.95 ppm, 2.78 ppm, 2.94 ppm, 3.58 ppm, 4.05 ppm, 4.38 ppm, 4.65 ppm, 4.91 ppm, 7.07 ppm, 7.22 ppm, 7.29 ppm, 7.43 ppm, 7.48 ppm, 7.60 ppm, 7.68 ppm, 7.74 ppm, 7.90 ppm, 8.09 ppm, 8.20 ppm, 8.25 ppm, 10.19 ppm, 11.73 ppm, and 11.84 ppm in the solution. 1 It is characterized by having an H NMR spectrum.

[0208]

[0236] Other embodiments may include one or more of the following features: a composition in which the composition is about 1 to 75% by weight of crystalline DMA solvate including both ends, for example, an embodiment in which the composition is about 1% by weight of crystalline DMA solvate and about 5% by weight of crystalline DMA solvate. The composition may include at least one pharmaceutically acceptable carrier or diluent.

[0209]

[0237] In some embodiments, methods for treating cancer are described.

[0210]

[0238] In some embodiments, a method for treating cancer reduces the size of a mammalian tumor. In some embodiments, the method inhibits the metastasis of a mammalian tumor. In some embodiments, the method inhibits tumor growth. In some embodiments, the method inhibits the metastasis of a mammalian tumor. In some embodiments, the method reduces or eliminates one or more symptoms associated with cancer.

[0211] definition

[0239] As used herein, the term “about” will be understood by those skilled in the art to mean up to plus or minus 10% of a number when used in relation to a number.

[0212]

[0240] The term "activator" or "active ingredient" refers to a compound in crystalline form, a mixture containing one or more compounds in crystalline form, or a mixture containing a compound in crystalline form and an amorphous form of compound 1.

[0213]

[0241] As used herein, the terms “substantially pure” and “substantially unpure” in relation to a particular polymorph of Compound 1 (or a mixture of two or more polymorphs) indicate that the polymorph (or mixture) contains less than 10% by weight, less than 5% by weight, less than 3% by weight, or less than 1% by weight of impurities, including other polymorphs of Compound 1. Such purity may be determined, for example, by powder X-ray diffraction.

[0214]

[0242] As used herein, the term “room temperature” refers to the temperature conditions typically encountered in a laboratory environment. This includes an approximate temperature range of about 18 to about 30°C.

[0215]

[0243] As used herein, the term “detectable quantity” refers to a quantity or quantity per unit volume that can be detected using conventional techniques such as X-ray powder diffraction, differential scanning calorimetry, HPLC, Fourier transform infrared spectroscopy (FT-IR), and Raman spectroscopy.

[0216]

[0244] The term “pharmaceutical composition” refers to a composition comprising about one polymorph of a compound described herein, as well as other chemical components such as physiologically / pharmaceutically acceptable carriers, diluents, vehicles and / or excipients.

[0217]

[0245] As used herein, the term “effective dose” refers to the amount of an activator that is effective in treating cancer in a mammal. In some embodiments, the mammal is a human.

[0218] The terms listed in Table 1 are defined herein as follows:

[0219] [Table 1]

[0220]

[0246] A novel crystalline form of Compound 1 is described herein. Compound 1 and a method for preparing it are described in U.S. Patent No. 9,586,974, which is incorporated herein by reference in its entirety.

[0221]

[0247] As described herein, it has been found that compound 1 can exist in multiple crystalline forms. These forms may be used in compositions in which the crystalline form of compound 1 is dissolved for the treatment of cancer. Each form may have advantages over others in terms of properties such as bioavailability, stability, and manufacturability. Novel crystalline forms of compound 1 have been discovered that are likely to be more suitable for bulk preparation and handling than other forms. Processes for preparing polymorphs of compound 1 that substantially do not contain other polymorphs of compound 1 are also described herein.

[0222]

[0248] In some embodiments, the solid crystal form may include more than one polymorphic crystal form. Those skilled in the art will recognize that the crystal form of a given compound can exist as a substantially pure form of a single polymorph, but can also exist as a crystal form comprising a mixture of two or more different polymorphic or amorphous forms. When the solid crystal form comprises two or more polymorphs, the X-ray diffraction pattern typically has peaks characteristic of each of the individual polymorphs. For example, a solid crystal form comprising two polymorphs typically has a powder X-ray diffraction pattern that is a superposition of two X-ray diffraction patterns corresponding to substantially pure polymorphic crystal forms. For example, the solid crystal form of compound 1 may comprise a first, second, third, fourth, or fifth polymorphic crystal form, and the solid crystal form comprises at least 10% by weight of the first polymorph. In further examples, the solid crystal form may comprise at least 20% by weight of the first polymorph. Even further examples may comprise at least 30% by weight, at least 40% by weight, or at least 50% by weight of the first polymorph. Those skilled in the art will recognize that many such combinations of several individual polymorphs and crystalline forms are possible, depending on the amount of variation.

[0223] II. Methods for treating cancer

[0249] This disclosure also provides a method for treating cancer in a mammal in need thereof, the method comprising the step of administering an effective amount of compound 1 in crystalline form to the mammal. Compound 1 in crystalline form may be crystalline form A hydrate, crystalline form B DMF solvate, crystalline form C anhydrous, crystalline form E DMSO solvate, crystalline form F DMA solvate, or a combination thereof.

[0224]

[0250] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a blood cancer.

[0225]

[0251] In some embodiments, cancer is a solid tumor cancer, and solid tumor cancers include fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endosarcoma, lymphangiosarcoma, lymphangiosarcoma, synoviomas, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, stomach cancer, oral cancer, nasal cancer, pharyngeal cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, These include sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, cholangiocarcinoma, choriocarcinoma, seminomas, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, small cell lung cancer, bladder cancer, lung cancer, epithelial carcinoma, glioma, glioblastoma multiforme, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pineal glandoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, skin cancer, melanoma, neuroblastoma, retinoblastoma, or hepatocellular carcinoma.

[0226]

[0252] In some embodiments, cancer is a blood cancer, and blood cancer is leukemia (for example, whether acute or chronic leukemia, e.g., lymphoblastic leukemia, myeloid leukemia, lymphocytic leukemia, myeloid leukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute monoblastic leukemia, acute erythroleukemia, acute megakaryoblastic leukemia) These include leukemia (such as myelomonocytic leukemia, acute nonlymphocytic leukemia, acute anaplastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, or hairy cell leukemia), lymphoma (e.g., Hodgkin's disease, non-Hodgkin lymphoma, Waldenström macroglobulinemia, heavy chain disease, or polycythemia vera), or myeloma (e.g., solitary plasmacytoma, extramedullary plasmacytoma, or multiple myeloma).

[0227]

[0253] It will be understood that the actual dose of a useful crystalline form of compound 1 in the compositions of this disclosure may vary depending on the specific polymorph used, the specific composition being formulated, the mode of administration, and the specific site, host, and disease being treated. Those skilled in the art can use conventional dose determination tests, taking into account experimental data on the drug, to determine the optimal dose for a given set of conditions. That level is typically sufficient to deliver about 100 to about 3000 μg / kg body weight to the recipient's plasma or serum.

[0228]

[0254] For oral administration, exemplary daily doses useful for treating cancer are approximately 0.001 to approximately 100 mg / kg body weight, in one embodiment approximately 0.01 to approximately 50 mg / kg body weight, and the course of treatment can be repeated at appropriate intervals. In practice of this disclosure, the most appropriate route of administration and the magnitude of the therapeutic dose may depend on the nature and severity of the disease being treated. The dose and frequency of administration may also vary according to the age, weight, and response of individual patients. Appropriate oral dosage forms may cover a dose range of 0.5 mg to 100 mg of the total daily dose of the active ingredient, administered as a single dose or in equal divided doses. In one embodiment, the amount of compound 1 in crystalline form in such a formulation is approximately 0.5 mg to approximately 20 mg, for example, approximately 1 mg to approximately 10 mg or approximately 1 mg to approximately 5 mg.

[0229] Mai. Pharmaceutical composition

[0255] The disclosure also provides a method for treating cancer in a mammal in need thereof, comprising the step of administering to the mammal an effective amount of a composition in which the crystalline form of compound 1 is dissolved in a suitable solvent, for example, disclosed herein.

[0230]

[0256] In some embodiments, administration is parenteral, and in some embodiments, administration is intravenous.

[0231]

[0257] The activators described herein (e.g., in crystalline form of Compound 1 or in solid form comprising two or more such forms) may be formulated into pharmaceutical compositions suitable for medical use in mammals. Any suitable route of administration may be used to provide a patient with an effective dose of any of the polymorphs of Compound 1. For example, oral or parenteral compositions may be used. Dosage forms include capsules, tablets, dispersants, suspensions, etc., including enteric-coated capsules and / or tablets, capsules and / or tablets containing enteric-coated pellets of polymorphs of Compound 1. In all dosage forms, polymorphs of Compound 1 can be mixed with other suitable components. The compositions may be conveniently provided in unit dosage forms and may be prepared by any method known in the pharmaceutical art. The pharmaceutical compositions of this disclosure typically comprise an effective amount of the activator and one or more inert, pharmaceutically acceptable carriers, and may also comprise any other therapeutic components, stabilizers, etc. The carriers are typically pharmaceutically acceptable in the sense that they are compatible with the other components of the composition and are not excessively harmful to their recipient. The composition may further contain diluents, buffers, binders, disintegrants, thickeners, lubricants, preservatives (including antioxidants), flavoring agents, taste masking agents, inorganic salts (e.g., sodium chloride), antimicrobial agents (e.g., benzalkonium chloride), sweeteners, antistatic agents, surfactants (e.g., polysorbates such as "TWEEN(trademark) 20" and "TWEEN(trademark) 80" and pluronics such as F68 and F88 available from BASF), sorbitan esters, lipids (e.g., long-chain, medium-chain, short-chain, and mixtures thereof), lecithin and other phospholipids such as phosphatidylcholine, phosphatidylethanolamine, fatty acids and fatty acid esters, steroids (e.g., cholesterol), and chelating agents (e.g., EDTA, zinc, and other suitable cations).Other pharmaceutical excipients and / or additives suitable for use in the compositions of this disclosure are listed in Remington: The Science & Practice of Pharmacy, 19th edition, Williams & Williams (1995), “Physician's Desk Reference,” 52nd edition, Medical Economics, Montvale, NJ (1998), and Handbook of Pharmaceutical Excipients, 3rd edition, edited by AH Kibbe, Pharmaceutical Press, 2000. The activators of this disclosure may be incorporated into compositions suitable for oral, rectal, topical, nasal, ocular, or parenteral administration (including intraperitoneal, intravenous, subcutaneous, or intramuscular injection).

[0232]

[0258] The amount of activator in a composition can vary depending on a variety of factors, including dosage form, the condition being treated, the target patient population, and other considerations, and is determined by those skilled in the art. In practice, this can vary widely depending, for example, on the specific activator, the severity of the condition being treated, the patient population, the stability of the composition, etc. The composition may contain some activator between about 0.001% by weight and about 99% by weight, in some embodiments about 0.01% by weight and about 5% by weight of the activator, and in some embodiments about 0.01% by weight and about 2% by weight of the activator, and may also depend on the relative amounts of excipients / additives contained in the composition.

[0233]

[0259] In some embodiments, the pharmaceutical composition can be administered in a conventional dosage form prepared by combining an effective amount of an active ingredient with one or more suitable pharmaceutical carriers, according to conventional procedures. These procedures may include mixing, granulating, and pressurizing or dissolving the appropriate components in the desired preparation.

[0234]

[0260] The pharmaceutical carrier used may be either solid or liquid. Exemplary solid carriers include, but are not limited to, lactose, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid, etc. Exemplary liquid carriers include syrup, peanut oil, olive oil, water, etc. Similarly, the carrier may contain alone or in combination with wax, ethyl cellulose, hydroxypropylmethyl cellulose, methyl methacrylate, etc., a time delay or sustained release substance known in the art such as glyceryl monostearate or glyceryl distearate.

[0235]

[0261] A variety of pharmaceutical forms can be used. For example, when a solid carrier is used, the preparation can be tableted, placed in hard gelatin capsules in powder or pellet form, or in the form of troches or lozenges. The amount of the solid carrier may vary, but is about 25 mg to about 1 g. When a liquid carrier is used, the preparation can be in the form of syrup, emulsion, soft gelatin capsule, sterile injection solution or suspension in ampoules or vials or non-aqueous liquid suspension.

[0236]

[0262] The active agent may be dissolved in a suitable co-solvent or combination of co-solvents. Examples of suitable co-solvents include, but are not limited to, alcohols, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin, etc. at a concentration in the range of about 0% to about 60% of the total volume.

[0237]

[0263] It will be understood that the actual dosage of the crystalline form of Compound 1 useful in the compositions of the present disclosure can vary depending on the particular polymorphic form used, the particular composition being formulated, the mode of administration as well as the particular site, host and disease being treated. One of ordinary skill in the art can use conventional dosage determination tests considering the experimental data for the drug and determine the optimal dosage for a given set of conditions. The level is typically an amount sufficient to provide about 100 to about 3000 μg / kg body weight to the plasma or serum of the recipient.

[0238]

[0264] For oral administration, the exemplary daily dose used is about 0.001 to about 100 mg / kg body weight, and in some embodiments, about 0.01 to about 50 mg / kg body weight, and the course of treatment can be repeated at appropriate intervals. The prodrug is typically administered at a weight level that is chemically equivalent to the weight level of the fully active form. In practice of this disclosure, the most appropriate route of administration and the magnitude of the therapeutic dose will depend on the nature and severity of the disease being treated. The dose and frequency of administration may also vary according to the age, weight, and response of individual patients. Appropriate oral dosage forms may cover a dose range of 0.5 mg to 100 mg of the total daily dose of the active ingredient, administered as a single dose or in equal divided doses. In some embodiments, the amount of compound 1 in crystalline form in such a composition is about 0.5 mg to about 20 mg, for example, about 1 mg to about 10 mg or about 1 mg to about 5 mg.

[0239]

[0265] The compositions of this disclosure may be manufactured in a manner known by the preparation of pharmaceutical compositions, for example, by using conventional techniques such as mixing, dissolving, granulation, sugar coating, polishing, emulsification, encapsulation, encapsulation, or freeze-drying. The pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers, which may be selected from excipients and auxiliaries that facilitate the processing of the active compound into a pharmaceutically usable preparation.

[0240]

[0266] For oral administration, the polymorphs of compound 1 can be readily formulated by combining the activator with a pharmaceutically acceptable carrier known in the art. Such carriers enable the compounds of this disclosure to be formulated as tablets, pills, coated tablets, capsules, gels, syrups, slurries, suspensions, etc., for oral intake by patients being treated. Pharmaceutical preparations for oral use may be obtained using a solid excipient mixed with the activator, the resulting mixture may be pulverized, and the mixture of granules may be processed after adding suitable adjuvants as desired to obtain a tablet or coated tablet core. Suitable excipients include sugars containing lactose, sucrose, mannitol, or sorbitol, and fillers such as cellulose preparations, e.g., corn starch, wheat starch, rice starch, potato starch, gelatin, rubber, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP). If desired, a disintegrant such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate, may be added.

[0241]

[0267] The sugar-coated tablet core is given an appropriate coating. For this purpose, a concentrated sugar solution may be used which may contain gum arabic, polyvinylpyrrolidone, carbopole gel, polyethylene glycol, and / or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture. Dyes or pigments may be added to the tablet or sugar-coated tablet coating to characterize different combinations of identifiers or activators.

[0242]

[0268] Pharmaceutical preparations for oral use include push-fit capsules made of gelatin, and soft-seal capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules may contain an active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and may also be mixed with a stabilizer. In soft capsules, the active ingredient may be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, a stabilizer may be added. All compositions for oral administration should be in a dosage suitable for such administration. For oral administration, compositions may take the form of tablets or lozenges formulated in a conventional manner.

[0243]

[0269] For intranasal or inhalation administration, the compound can be conveniently delivered in the form of an aerosol spray from a pressurized pack or nebulizer with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of pressurized aerosol formulations, the dose unit may be determined by providing a valve for delivering the measured amount. Gelatin capsules and cartridges for use in inhalers or air injectors may be formulated, containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0244]

[0270] The activator may be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. The composition for injection may be provided in unit dosage forms, such as ampoules or multi-dose containers, with added preservatives. The composition may take the form of a suspension, solution or emulsion in an oily or aqueous vehicle, and may contain formulation agents such as suspending, stabilizing and / or dispersing agents.

[0245]

[0271] Compositions for intravenous administration may include a carrier selected from the group consisting of a water-soluble organic solvent, a nonionic surfactant, a water-insoluble lipid, an organic lipid / semi-solid, and a phospholipid. The water-soluble organic solvent may be selected from, for example, polyethylene glycol 300, polyethylene glycol 400, ethanol, propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethyl sulfoxide. The nonionic surfactant may be selected from Cremophor EL, Cremophor RH40, Cremophor RH60, d-α-tocopherol polyethylene glycol 1000 succinate, polysorbate 80, Solutol HS15, sorbitan monooleate, poloxamer 407, Labrifil M-1944CS, Labrafil M-2125CS, Labrasol, Gellucire 44 / 14, Softigen 767, and mono and di fatty acid esters of PEG300, 400, or 1750. Water-insoluble lipids are selected from castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, and medium-chain triglycerides from coconut oil and palm seed oil. Organic liquids and semi-solids may be selected from beeswax, d-α-tocopherol, oleic acid, and medium-chain mono and diglycerides. Phospholipids are selected from lecithin, hydrogenated soybean phosphatidylcholine, distearoyl phosphatidylglycerol, L-α-dimyristoyl phosphatidylcholine and L-α-dimyristoyl phosphatidylglycerol and others disclosed herein.

[0246]

[0272] The carriers include osmotic regulators containing dimethylacetamide, dimethyl sulfoxide, dimethylformamide, cyclodextrin and their derivatives, albumin, buffers, salts, and glycerol; oils and lipids containing medium-chain and long-chain triglycerides and mixtures thereof; and natural and synthetic emulsifiers containing phospholipids and phosphatidylcholine and mixtures thereof.

[0247]

[0273] For compositions intended for intravenous delivery, the frequency of administration for the active form of compound 1 may be once every 4 weeks, or once or twice per week.

[0248]

[0274] Other pharmaceutical compositions for parenteral administration may, for example, include a suspension of the activator and may be prepared as a suitable oily injection suspension. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. The aqueous injection suspension may also include a substance that increases the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. The suspension may also include a suitable stabilizer or agent that increases the solubility of the activator to enable the preparation of a highly concentrated solution.

[0249]

[0275] For ocular administration, the activator can be delivered by a pharmaceutically acceptable ophthalmic vehicle such that the compound remains in contact with the ocular surface for a sufficient period to allow the compound to penetrate into the cornea and internal regions of the eye, including, for example, the anterior chamber, posterior chamber, vitreous humor, aqueous humor, vitreous fluid, cornea, iris / ciliary body, lens, choroid / retina, and sclera. The pharmaceutically acceptable ophthalmic vehicle may be, for example, an ointment, vegetable oil, or encapsulating substance. The activator of this disclosure may also be injected directly into the vitreous humor and aqueous humor or subtenon's capsule.

[0250]

[0276] Alternatively, the active ingredient may be in powder form for preparation with a suitable vehicle before use, such as sterile, pyrogen-free water. The compound may also be incorporated into rectal or vaginal compositions, such as suppositories or retaining enemas, which may contain conventional suppository bases, such as cocoa butter or other glycerides.

[0251]

[0277] In addition to the compositions described above, the polymorphs may also be formulated as depot preparations. Such long-acting compositions may be administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Therefore, for example, the polymorphs may be formulated with a suitable polymer or hydrophobic substance (e.g., as an emulsion in an acceptable oil) or an ion exchange resin, or as a sparingly soluble derivative, for example, as a sparingly soluble salt.

[0252]

[0278] In addition, the polymorphs of compound 1 may be delivered using a sustained-release system such as a semipermeable matrix of a solid hydrophobic polymer containing the therapeutic agent. Various sustained-release materials have been established and are known to those skilled in the art. Depending on their chemical properties, sustained-release capsules may release the compound for several weeks to more than 100 days.

[0253]

[0279] The pharmaceutical composition may also include a suitable solid-phase or gel-phase support or excipient. Examples of such supports or excipients include polymers such as calcium carbonate, calcium phosphate, sugars, starch, cellulose derivatives, gelatin, and polyethylene glycol. [Examples]

[0254] IV. Methods for producing polymorphs

[0280] The following examples further illustrate the preparation and characterization of individual polymorphic forms of Compound 1, but are not intended to limit the scope of the present disclosure as described herein or claimed herein. Unless otherwise specified, all temperatures are given in degrees Celsius, and all parts and percentages are by weight.

[0255]

[0281] Example 1 Preparation of Compound 1 Crystalline Form A Hydrate For example, 251 mg of compound 1 was placed in an 8 mL glass vial, followed by 2.0 mL of methanol:water (v / v) in a ratio of approximately 95:5. The resulting slurry was magnetically stirred at 40°C for approximately 2 days. The slurry was vacuum filtered, and the solid was air-dried at room temperature for 15 minutes.

[0256]

[0282] Example 2 Preparation of Compound 1 Crystal Form B DMF Solvate 19.8 mg of Example Crystal Form A Hydrate was transferred to a vial, and 1 mL of DMF was added. The resulting mixture was magnetically stirred at room temperature. The mixture was initially a clear solution, but after several hours, a solid formed. The resulting slurry was centrifuged, the solid was collected, and air-dried overnight.

[0257]

[0283] Example 3 Preparation of Compound 1 Crystal Form C Anhydrate 20.2 mg of Crystal Form A Hydrate was transferred to a vial. An aliquot of acetonitrile to a total of 16 mL was added. The resulting mixture was magnetically stirred at 40 °C for about one week. When sufficient solid had formed, the resulting slurry was centrifuged, the solid was collected, and dried in a vacuum desiccator for several hours.

[0258]

[0284] Example 4 Preparation of Compound 1 Crystal Form E DMSO Solvate 20.3 mg of Example Crystal Form A Hydrate was transferred to a vial. 1 mL of DMSO was added, and the resulting mixture was magnetically stirred at room temperature. Water was added dropwise to the resulting solution, and it became turbid after a few drops. The turbid mixture was maintained on a stirring plate at room temperature for about one day. When sufficient solid had formed, the resulting slurry was centrifuged, the solid was collected, and dried in a vacuum desiccator for several hours.

[0259]

[0285] Example 5 Preparation of Compound 1 Crystal Form F DMA Solvate 12.4 mg of each of Example Crystal Form A Hydrate and Crystal Form C Anhydrate was weighed into a vial, and 0.5 mL of dry DMA:H2O in about 70:about 30 was added. The mixture was magnetically stirred at room temperature for about one week. The resulting slurry was centrifuged, the solid was collected, and dried in a vacuum desiccator for several hours.

[0260]

[0286] Example 6 Characterization of additional XRPD peaks in crystalline form A hydrate. In one sample of Compound 1 Crystal Form A hydrate, a small broad peak at approximately 7.1°²θ was observed in the XRPD pattern. The nature of this peak is unknown. Compound 1 Crystal Form A hydrate was slurryed at room temperature for approximately 2 days in both methanol (Figure 24A) and methanol:water (v / v) at approximately 95:5 (Figure 24B) to determine whether the peak disappeared (Table 22). In small amounts (approximately 30 mg) in both solvent systems, the XRPD pattern of the substance remained that of Crystal Form A hydrate, and the 7.1°²θ peak was retained. In larger experiments (approximately 250 mg) in methanol:water (v / v) at approximately 95:5, the peak became smaller (Figure 24C). The NMR data did not show evidence of impurities.

[0261] [Table 2]

[0262]

[0287] Example 7 Solid state stability of Compound 1 crystalline form A hydrate, Compound 1 crystalline form C anhydrous, and amorphous Compound 1. The relative stability of crystalline form A hydrate and crystalline form C anhydrous compound 1 was evaluated in ethanol and ethanol / water at ambient temperatures between ~50°C. The results showed that crystalline form A hydrate was converted to crystalline form C anhydrous except when the water activity of the solvent exceeded 0.31. When crystalline form A hydrate was analyzed after being slurryed for 4 days, it was converted to crystalline form C anhydrous in ethanol at approximately 50°C.

[0263]

[0288] Table 23 summarizes the attempts to prepare crystalline form C anhydrous and amorphous material. Crystalline form C anhydrous was prepared by slurring crystalline form A hydrate in anhydrous ethanol at 40°C for approximately 2 days (Sample 1, Figure 25A). Attempts to prepare amorphous material by cooling precipitation and freeze-drying were unsuccessful. Two of the precipitation experiments did not produce solids, while the other two produced materials with XRPD patterns corresponding to crystalline forms A and F, respectively (Sample 2, Figure 25B; Sample 4, Figure 25D). The freeze-drying experiment produced a material with an XRPD pattern corresponding to crystalline form E DMSO solvate (Figure 25C).

[0264] [Table 3]

[0265]

[0289] Crystalline form A hydrate was prepared according to Example 1.

[0266]

[0290] The DSC curve for crystalline form A hydrate showed a broad endothermic pattern with a maximum signal at approximately 96°C (Figure 26). The TG curve shows a corresponding weight loss of 2.8% up to 100°C, corresponding to approximately 0.94 moles of water per mole of compound 1 crystalline form A hydrate. This is consistent with the thermal data for crystalline form A hydrate from polymorph screening, which shows a broad DSC endothermic pattern and a TG weight loss of approximately 2.6% below 100°C.

[0267]

[0291] To prepare the anhydrous crystalline form C, 249 mg of compound 1 crystalline form A hydrate was placed in an 8 mL glass vial, followed by 2.0 mL of anhydrous ethanol. The resulting slurry was magnetically stirred at 40°C for approximately 2 days. The slurry was vacuum filtered, and the solid was air-dried at room temperature for 15 minutes.

[0268]

[0292] The DSC curve for crystalline form C anhydrous shows no event below the decomposition point of approximately 275°C (Figure 27). The TG curve shows a small weight loss of approximately 0.8% up to 250°C, suggesting that it is anhydrous. This is consistent with the thermal data for crystalline form C anhydrous from the polymorph screening report. Compound 1 crystalline form C anhydrous is unsolvated.

[0269] [Table 4]

[0270]

[0293] Example 8 Examples: Stability study of crystalline form A hydrate and crystalline form C anhydrous Samples of each of the crystal morphologies A and C were placed in uncapped vials and exposed to 25°C / 60%RH and 40°C / 75% relative humidity ("RH") for 4 weeks (Table 24). The resulting samples were analyzed by XRPD at T=1, 2, and 4 weeks to evaluate their physical stability. No crystal morphology changes were observed after 4 weeks.

[0271] [Table 5]

[0272]

[0294] Example 9 Conversion rate from crystalline form A (hydrate) to crystalline form C (anhydrous) The conversion rate from crystalline form A hydrate to crystalline form C anhydrous was investigated in ethanol at approximately 50°C (Table 25). Slurries were prepared using compound 1 crystalline form A hydrate as the starting material. Each slurry contained approximately 20 mg of compound 1 crystalline form A hydrate and 1 mL of anhydrous ethanol. Each slurry was magnetically stirred at approximately 50°C, and then the solid was collected by vacuum filtration at a given time. The obtained solid was immediately analyzed by XRPD. At T=1 hour, the sample was completely converted to crystalline form C anhydrous (Figure 4).

[0273] [Table 6]

[0274]

[0295] Example 10 Example Equipment AX-ray powder diffraction (XRPD)

[0296] The Rigaku SmartLab X-ray diffractometer was configured with a Bragg-Brentano reflection geometry featuring a beam stop and knife edge to reduce incident beam and air scattering. Filters were not used for crystalline crystalline C anhydrous and crystalline crystalline E DMSO solvate. A rotation speed of 17 rpm was used for the analysis of crystalline crystalline C anhydrous. Other parameters were the same as those listed in Table 27.

[0275] [Table 7]

[0276] B. Crystalline form of compound 1

[0297] Several crystalline forms of compound 1 are described herein. Each crystalline form can be characterized by one or more of the following: powder X-ray diffraction patterns (e.g., X-ray diffraction peaks at various diffraction angles (2θ)), 1 Melting point onset (and dehydration onset for hydrated forms) as described by 1H NMR spectroscopy, endothermic differential scanning calorimetry (DSC) thermograms, thermal stability as described by thermogravimetric analysis (TG), hygroscopic properties as described by dynamic vapor adsorption (DVS) measurements, IR spectral diagram patterns, Raman spectral diagram patterns, and physical and chemical storage stability according to methods known in the art or described herein.

[0277]

[0298] Those skilled in the art will understand that the peak position (2θ) of an XRPD typically exhibits variations of as much as 0.1–0.2 degrees (2θ), depending, for example, on the solvent used and / or on the instrument used to measure the diffraction. Therefore, when a peak position (2θ) is reported, those skilled in the art will recognize that such a figure is intended to encompass such variations. Furthermore, when it is stated that a polymorph of this disclosure has a powder X-ray diffraction pattern essentially the same as that shown in a given figure, the term “essentially the same” is also intended to encompass such variations in diffraction peak position.

[0278]

[0299] Furthermore, those skilled in the art will understand that relative peak intensities exhibit variations due to inter-instrument variability as well as variations resulting from the degree of crystallinity, orientation, prepared sample surface, purity of the sample being analyzed, and other factors known to those skilled in the art, and should be considered only as qualitative measurements. Those skilled in the art will also understand that measurements using different wavelengths result in different shifts following the Bragg equation -nλ=2d sinθ. Such further XRPD patterns produced by the use of alternative wavelengths are considered alternative representations of the XRPD patterns of crystalline materials in the embodiments described herein and are therefore within the scope of these embodiments.

[0279]

[0300] The different polymorphs of approximately one compound described herein were characterized using a Rigaku SmartLab X-ray diffractometer configured with a Bragg-Brentano reflection geometry equipped with a beam stop and knife edge to reduce incident beam and air scattering. Filters were not used for crystalline form C anhydrous and crystalline form E DMSO solvate. A rotation speed of 17 rpm was used for the analysis of crystalline form C anhydrous. Other parameters were the same as those listed in Table 2.

[0280] [Table 8]

[0281]

[0301] Different polymorphs of compound 1 described herein can also be characterized using solid-state NMR spectroscopy according to methods known in the art or described herein. For example, 1 ¹H NMR spectra were acquired using a Bruker Avance II 400 spectrometer. Samples were prepared by dissolving the substance in DMSO-d6. The solutions were placed in individual 5 mm NMR tubes for subsequent spectral acquisition. Temperature-controlled (298 K) spectra were acquired using the Avance II 400. 1 ¹H NMR spectra were obtained using a 5 mm cryoprobe operating at an observation frequency of 400.18 MHz. Each spectrum was processed using TopSpin version 4.1.4, and the chemical shift of the residual DMSO-d6 (2.5 ppm) peak was referenced.

[0282]

[0302] Different crystalline forms of compound 1 were also distinguished using differential scanning calorimetry (DSC). DSC measures the difference in thermal energy uptake between the sample and a suitable reference as the temperature increases. For example, for the measurement of a solid powder sample, the reference may be an empty sample pan of the type used to prepare the sample. A DSC thermogram can also be characterized by endothermic (indicating energy uptake) and exothermic (indicating energy release) reactions as the sample is heated, typically. Depending on several factors, the observed endothermic reaction may vary by about 0.01–5°C for crystalline polymorphs that melt above or below the endothermic reaction, such as those shown in the accompanying diagram (Figure). Factors that cause such differences include, for example, the heating rate (e.g., scanning rate) at which the DSC analysis is performed, the method by which the DSC start temperature is defined and determined, the calibration standard used, instrument calibration, relative humidity, and the chemical purity of the sample. For any given sample, the observed endothermic reaction may differ from instrument to instrument, but this is within the range described herein, provided that the instruments are similarly calibrated.

[0283]

[0303] DSC analysis was performed using a TA Instruments Q2500 Discovery Series instrument. Instrument temperature calibration was performed using indium. The DSC cell was maintained under nitrogen purging of approximately 50 mL per minute during analysis. The sample was placed in a standard crimped aluminum pan and heated from approximately 25°C to 250°C at a rate of 10°C per minute. The crystalline form A hydrate was heated to 350°C.

[0284]

[0304] Different polymorphic forms of a compound may have different hygroscopic properties. For example, the crystalline forms of compound 1 were characterized based on their hygroscopic properties using dynamic vapor adsorption measurements with a TA Instruments Q5000 dynamic vapor adsorption analyzer. Sample weights of less than 10 mg were loaded into metal-coated quartz pans for analysis. Samples were equilibrated at 25°C and 5% relative humidity (RH), and then analyzed in 10% RH increments from 5 to 95% RH (adsorption cycle) and from 95 to 5% RH (desorption cycle). Movement from one increment to the next was made after the equilibrium criterion of a 0.01 wt% change in 5 minutes was met, or after 90 minutes if the equilibrium criterion was not met. Wt% change values ​​were calculated using Microsoft Excel®.

[0285]

[0305] The five polymorphic crystalline forms of compound 1 were identified and characterized as shown in the figure. These crystalline forms are referred to as polymorphic crystalline forms A, B, C, E, and F. The polymorphs, pharmaceutical compositions containing one or more polymorphs, and methods of using the polymorphs and pharmaceutical compositions are described in more detail in the following sections and examples.

[0286] A. Compound 1, polymorphic Form A hydrate

[0306] Compound 1, crystalline form A hydrate is a slightly hygroscopic hydrated crystalline substance and is a variable hydrate between hemihydrate and monohydrate.

[0287]

[0307] KF analysis of compound 1 crystalline form A hydrate showed a water content of 2.4%.

[0288]

[0308] We successfully indexed the hydrate of compound 1 in crystalline form A, demonstrating that it is a pure crystalline phase.

[0289]

[0309] Figure 8 shows the DMSO-d6 1 The 1H NMR spectrum matches the chemical structure of compound 1-crystal form A hydrate with 0.03 mol of DMF and 0.03 mol of hexane. This suggests that approximately 2.1% of the 2.6% weight loss observed in TGA is attributable to water, which is 0.7 mol per molecule of compound 1-crystal form A hydrate. 1 The list of 1H NMR peaks is shown in Table 3.

[0290] [Table 9]

[0291]

[0310] Compound 1 crystalline form A hydrate exhibited the XRPD pattern shown in Figure 2. The XRPD pattern of Compound 1 crystalline form A hydrate is expressed in terms of degree (2θ) and relative intensity measured with a Rigaku SmartLab X-ray diffractometer. Table 4 shows the XRPD analysis of Compound 1 crystalline form A hydrate, with selected peaks specific to Compound 1 crystalline form A hydrate shown in bold.

[0292] [Table 10]

[0293]

[0311] For solid compositions containing compound 1 crystalline form A hydrate, the compound 1 crystalline form A hydrate in the product can be identified by analyzing the solid composition using XRPD. This can be done by deconvolution of the XRPD data obtained from the prepared product. This can be achieved by subtracting known excipient signals from the XRPD data of the prepared product. In addition, various metrological techniques can be used to identify compound 1 crystalline form A hydrate in solid compositions, such as principal component analysis. Since the XRPD peaks belonging to compound 1 crystalline form A hydrate may overlap with the XRPD peaks of some of the excipients used in the composition, such analysis may be necessary to identify them.

[0294]

[0312] The DSC thermogram of compound 1 crystalline form A hydrate (Figure 3) shows a broad endothermic reaction at approximately 78°C, which corresponds to the weight loss observed in the TG data. The substance melts between 279 and 281°C, accompanied by decomposition events.

[0295]

[0313] The TG thermogram of compound 1 crystalline form A hydrate (Figure 4) shows a weight loss of 2.6% up to 70°C.

[0296]

[0314] In addition, compound 1 crystalline form A hydrate is slightly hygroscopic (Figure 5), exhibiting a weight increase of less than 0.5% up to 95% relative humidity (RH). This weight increase is compared to the dehydrated crystalline form A hydrate exposed to low RH at the start of the DVS run. Equilibrium was not reached in the DVS data, suggesting that weight increases exceeding 0.5% may be possible with longer equilibrium times.

[0297]

[0315] The infrared (Figure 6) and Raman (Figure 7) spectra are consistent with the chemical structure of compound 1. Tables 5 and 6 show the IR peaks and Raman shifts, respectively. In addition, several weak, broad peaks between 3420 and 3650 cm⁻¹ indicate the presence of water, supporting the fact that crystalline form A is a hydrate. Selected peaks / shifts specific to crystalline form A of compound 1 are shown in bold.

[0298] [Table 11]

[0299] [Table 12]

[0300]

[0316] For compositions containing compound 1 crystalline form A hydrate, the compound 1 crystalline form A hydrate in the product can be identified by analyzing the composition by IR and / or Raman spectroscopy. This can be done by deconvolution of the IR and / or Raman spectroscopy obtained from the prepared product. This can be achieved by subtracting known excipient signals from the IR and / or Raman spectroscopy of the prepared product. In addition, compound 1 crystalline form A hydrate in a composition can be identified using various metric chemical techniques, such as principal component analysis. Since the IR and / or Raman signals belonging to compound 1 crystalline form A hydrate may overlap with the IR and / or Raman signals of some of the excipients used in the composition, such analysis may be necessary to identify them.

[0301]

[0317] Table 7 summarizes the characteristics of compound 1 crystalline form A hydrate.

[0302] [Table 13]

[0303] B. Compound 1, polymorphic crystalline form B DMF solvate

[0318] Compound 1 Crystal Form B DMF solvate in DMSO-d6 1 ¹H NMR analysis (Figure 12) is consistent with the chemical structure of compound 1 and the amount of DMF per molecule of compound 1 (1.6 moles). The crystalline form of compound 1 is B. The DMF solvate in DMSO-d6... 1 The 1H NMR spectrum is shown in Figure 12. 1The list of 1H NMR peaks is shown in Table 8.

[0304] [Table 14]

[0305]

[0319] Compound 1, crystalline form B, DMF solvate exhibited the XRPD pattern shown in Figure 9. Compound 1, crystalline form B, DMF solvate is a crystalline DMF solvate. The XRPD pattern of Compound 1, crystalline form B, DMF solvate is expressed in terms of degree (2θ) and relative intensity measured with a Rigaku SmartLab X-ray diffractometer. Table 9 shows the XRPD analysis of Compound 1, crystalline form B, DMF solvate, with selected peaks specific to Compound 1, crystalline form B, DMF solvate shown in bold.

[0306] [Table 15]

[0307]

[0320] For solid compositions containing compound 1 crystalline form B DMF solvate, the compound 1 crystalline form B DMF solvate in the product can be identified by analyzing the solid composition using XRPD. This can be done by deconvolution of the XRPD data obtained from the prepared product. This can be achieved by subtracting the signals of known excipients from the XRPD data of the prepared product. In addition, various metrological techniques can be used to identify compound 1 crystalline form B DMF solvate in solid compositions, such as principal component analysis. Since the XRPD peaks belonging to compound 1 crystalline form B DMF solvate may overlap with the XRPD peaks of some of the excipients used in the composition, such analysis may be necessary to identify them.

[0308]

[0321] The DSC thermogram of compound 1, crystalline form B, DMF solvate (Figure 10) shows broad endothermic activity at 147°C.

[0309]

[0322] The TG thermogram of compound 1, crystalline form B, DMF solvate (Figure 11) shows a weight loss of 18.3% up to 185°C.

[0310]

[0323] In addition, the indexing of Compound 1 Crystal Form B DMF solvate was successful, suggesting a pure crystalline phase. Based on volume considerations, it was determined that Compound 1 Crystal Form B DMF solvate is a solvate.

[0311]

[0324] Table 10 summarizes the characteristics of the DMF solvate of compound 1 in crystalline form B.

[0312] [Table 16]

[0313] C. Compound 1, polymorphic crystalline form C anhydrous

[0325] Compound 1, crystalline form C, anhydrous is an anhydrous crystalline substance. The XRPD diffractogram for Compound 1, crystalline form C, anhydrous is shown in Figure 13.

[0314]

[0326] The DSC thermogram of compound 1 crystalline form C anhydrous (Figure 14) shows broad endothermic activity at 100.55°C.

[0315]

[0327] The TG thermogram of compound 1 crystalline form C anhydrous (Figure 15) shows a minimum weight loss of 0.4% up to 135°C.

[0316]

[0328] The DVS data for compound 1 crystalline form C anhydrous (Figure 16) shows a weight increase of 0.35% between 5 and 95% RH.

[0317]

[0329] The indexing of compound 1 in crystalline form C anhydrous was successful, demonstrating that it is a pure crystalline phase. Acetonitrile was not part of the crystal lattice, based on volume considerations.

[0318]

[0330] Compound 1, crystalline form C, anhydrous in DMSO-d6 1The 1H NMR spectrum (Figure 19) is consistent with 0.07 moles of acetonitrile (ACN) per mole of compound 1, corresponding to the weight loss observed from the chemical structure and TG data of compound 1 in DMSO-d6. 1 The list of 1H NMR peaks is shown in Table 11.

[0319] [Table 17]

[0320]

[0331] Compound 1 (crystalline form C) anhydrous exhibited the XRPD pattern shown in Figure 13. The XRPD pattern of Compound 1 (crystalline form C) anhydrous is expressed in terms of degree (2θ) and relative intensity measured with a Rigaku SmartLab X-ray diffractometer. Table 12 shows the XRPD analysis of Compound 1 (crystalline form C) anhydrous, with selected peaks specific to Compound 1 (crystalline form C) anhydrous shown in bold.

[0321] [Table 18]

[0322]

[0332] For solid compositions containing compound 1 in crystalline form C, the anhydrous compound 1 in crystalline form C can be identified in the product by analyzing the solid composition using XRPD. This can be achieved by deconvolution of the XRPD data obtained from the prepared product. This can be achieved by subtracting the signals of known excipients from the XRPD data of the prepared product. In addition, various metrological techniques can be used to identify the anhydrous compound 1 in crystalline form C in solid compositions, such as principal component analysis. Since the XRPD peaks belonging to the anhydrous compound 1 in crystalline form C may overlap with the XRPD peaks of some of the excipients used in the composition, such analysis may be necessary to identify them.

[0323]

[0333] The infrared (Figure 17) and Raman (Figure 18) spectra are consistent with the chemical structure of compound 1. Tables 13 and 14 show the IR peaks and Raman shifts, respectively, with selected peaks / shifts specific to the crystalline form C anhydride of compound 1 shown in bold.

[0324] [Table 19]

[0325] [Table 20]

[0326]

[0334] For compositions containing Compound 1 Crystal Form C Anhydride, the Compound 1 Crystal Form C Anhydride in the product can be identified by analyzing the composition using IR and / or Raman spectroscopy. This can be achieved by deconvolution of the IR and / or Raman spectroscopy obtained from the composition. This can be achieved by subtracting known excipient signals from the IR and / or Raman spectroscopy of the crystalline compounded product. In addition, various metric chemical techniques can be used to identify Compound 1 Crystal Form C Anhydride in the product, such as principal component analysis. Since the IR and / or Raman signals belonging to Compound 1 Crystal Form C Anhydride may overlap with the IR and / or Raman signals of some of the excipients used in the composition, such analysis may be necessary to identify them.

[0327]

[0335] Table 15 summarizes the characteristics of compound 1, crystalline form C, in its anhydrous form.

[0328] [Table 21]

[0329] D. Compound 1, polymorphic crystalline form E DMSO solvate

[0336] Compound 1, in crystalline form E, is crystalline and is a DMSO solvate.

[0330]

[0337] Indexing of compound 1, crystalline form E, DMSO solvate was unsuccessful, suggesting that the substance is not in a pure crystalline phase. However, the XRPD pattern suggests a solvate, with a large amount of disordered scattering observed between 14 and 28°²θ and no peaks observed beyond 30°²θ.

[0331]

[0338] Compound 1 Crystal Form E DMSO solvate contains approximately 1.6 moles of DMSO per mole in DMSO-d6 1 Observed in the 1H NMR spectrum (Figure 21). Table 16 shows the results in DMSO-d6. 1 The 1H NMR peak list is shown.

[0332] [Table 22]

[0333]

[0339] Compound 1 (crystalline form E) DMSO solvate exhibited the XRPD pattern shown in Figure 20. The XRPD pattern of Compound 1 (crystalline form E) DMSO solvate is expressed in terms of degree (2θ) and relative intensity measured with a Rigaku SmartLab X-ray diffractometer. Table 17 shows the XRPD analysis of Compound 1 (crystalline form E) DMSO solvate, with selected peaks specific to Compound 1 (crystalline form E) DMSO solvate shown in bold.

[0334] [Table 23]

[0335]

[0340] For solid compositions containing compound 1 crystalline form E DMSO solvate, the compound 1 crystalline form E DMSO solvate in the solid composition can be identified by analyzing the solid composition using XRPD. This can be achieved by deconvolution of the XRPD data obtained from the composition. This can be achieved by subtracting the signals of known excipients from the XRPD data of the prepared product. In addition, various metrological techniques can be used to identify compound 1 crystalline form E DMSO solvate in a composition, such as principal component analysis. Since the XRPD peaks belonging to compound 1 crystalline form E DMSO solvate may overlap with the XRPD peaks of some of the excipients used in the composition, such analysis may be necessary to identify them.

[0336]

[0341] Table 18 summarizes the characteristics of compound 1, crystalline form E, DMSO solvate.

[0337] [Table 24]

[0338] E. Compound 1, polymorphic crystalline form F DMA solvate

[0342] Compound 1, in its crystalline form, is a crystalline DMA solvate.

[0339]

[0343] The crystalline form of compound 1, F DMA solvate, was successfully indexed, suggesting a pure crystalline phase. Based on volume considerations, the crystalline form of F DMA solvate was consistent with a mono-DMA solvate.

[0340]

[0344] In DMSO-d6 1 The 1H NMR result (Figure 23) shows 0.82 moles of DMA per molecule of compound 1, which is consistent with the indexing result. Table 19 shows the 1H NMR peak list in DMSO-d6.

[0341] [Table 25]

[0342]

[0345] Compound 1 (crystalline form F) DMA solvate exhibited the XRPD pattern shown in Figure 22. The XRPD pattern of Compound 1 (crystalline form F) DMA solvate is expressed in terms of degree (2θ) and relative intensity measured with a Rigaku SmartLab X-ray diffractometer. Table 20 shows the XRPD analysis of Compound 1 (crystalline form F) DMA solvate, with selected peaks specific to Compound 1 (crystalline form F) DMA solvate shown in bold.

[0343] [Table 26]

[0344]

[0346] For solid compositions containing compound 1 crystalline form F DMA solvate, the compound 1 crystalline form F DMA solvate in the solid composition can be identified by analyzing the solid composition using XRPD. This can be achieved by deconvolution of the XRPD data obtained from the composition. This can be achieved by subtracting known excipient signals from the XRPD data of the prepared product. In addition, various metrological techniques can be used to identify compound 1 crystalline form F DMA solvate in a composition, such as principal component analysis. Since the XRPD peaks belonging to compound 1 crystalline form F DMA solvate may overlap with the XRPD peaks of some of the excipients used in the composition, such analysis may be necessary to identify them.

[0345]

[0347] Table 21 summarizes the characteristics of the crystalline form F DMA solvate of compound 1.

[0346] [Table 27]

[0347] C. Differential Scanning Calorimetry (DSC)

[0348] DSC analysis was performed using a TA Instruments Q2500 Discovery Series instrument. Instrument temperature calibration was performed using indium. The DSC cell was maintained under nitrogen purging of approximately 50 mL per minute during analysis. The sample was placed in a standard crimped aluminum pan and heated from approximately 25°C to 250°C at a rate of 10°C per minute. The crystalline form A hydrate was heated to 350°C.

[0348] D. Thermogravimetric analysis (TGA)

[0349] TG analysis was performed using a TA Instruments Q50 Discovery Series instrument. Nitrogen purging was approximately 10 mL per minute using a balance and approximately 90 mL per minute using a heating furnace. The sample was placed in a platinum pan with pre-weighed tare weights and heated at a rate of 10°C per minute to approximately 25°C to 350°C.

[0349] E. Dynamic Vapor Adsorption (DVS) Analysis

[0350] DVS analysis was performed using a TA Instruments Q5000 dynamic vapor adsorption analyzer. Sample weights of less than 10 mg were loaded into a metal-coated quartz pan for analysis. Samples were equilibrated at 25°C and 5% relative humidity (RH), and then analyzed in 10% RH increments from 5 to 95% RH (adsorption cycle) and from 95 to 5% RH (desorption cycle). Movement from one increment to the next was performed after the equilibrium criterion of a 0.01 wt% change in 5 minutes was met, or after 90 minutes if the equilibrium criterion was not met. Wt% change values ​​were calculated using Microsoft Excel®.

[0350] F. Infrared (IR) spectroscopy

[0351] IR spectroscopy was performed using a Thermo Scientific iS50 Fourier Transform (FT) IR spectrophotometer equipped with a deuterated triglycine sulfate (DTGS) detector, potassium bromide (KBr) beam splitter, and Polaris® long-life IR source at 4000 cm⁻¹. -1 ~400cm -1A diamond attenuated total internal reflection (ATR) sampling accessory with a spectral range was used. Each spectrum was measured at 2 cm. -1 This is the result of 128 integrated scans acquired at a resolution of . A single-beam background scan of air was acquired before the sample scan to enable spectral display in log1 / R units. Wavelength calibration was performed using polystyrene. Spectral data was acquired, processed, and evaluated using the OMNIC v9.11 software package (Thermo-Nicolet).

[0351] G. Fourier Transform (FT) Raman Spectroscopy

[0352] Raman spectroscopy was performed using a Nicolet iS50 Raman module equipped with a 1064 nm near-infrared laser. The system consisted of an indium gallium arsenide (InGaAs) detector and a calcium fluoride (CaF2) beam splitter. Each sample was placed on an automated XYZ stage and analyzed using laser power adjusted to optimize signal intensity while avoiding damage to the sample. Raman spectra were obtained at 3700 cm⁻¹. -1 ~100cm -1 Over the spectral range of 2 cm -1 Data was collected using 256 signal-averaged scans at a resolution of [resolution value]. Data acquisition and processing were performed using OMNIC v9.11 software.

[0352] H. 1 H nuclear magnetic resonance (NMR) spectroscopy

[0353] 1 ¹H NMR spectra were acquired using a Bruker Avance II 400 spectrometer. Samples were prepared by dissolving the substance in DMSO-d6. The solutions were placed in individual 5 mm NMR tubes for subsequent spectral acquisition. Temperature-controlled (298 K) spectra were acquired using the Avance II 400. 1 ¹H NMR spectra were obtained using a 5 mm cryoprobe operating at an observation frequency of 400.18 MHz. Each spectrum was processed using TopSpin version 4.1.4, and the chemical shift of the residual DMSO-d6 (2.5 ppm) peak was referenced.

Claims

1. Compound 1 Crystalline Form A Hydrate.

2. A hydrate of compound 1 crystalline form A according to claim 1, having substantially the X-ray powder diffraction pattern shown in Figure 2.

3. The compound 1 crystalline form A hydrate according to claim 1, further characterized by an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) 6.1±0.2°, 8.7±0.2°, 9.7±0.2°, 13.7±0.2°, 13.9±0.2°, 19.4±0.2°, 23.4±0.2°, and 25.4±0.2°.

4. The compound 1 crystalline form A hydrate according to claim 1, further characterized by an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) 6.1±0.2°, 8.7±0.2°, 9.7±0.2°, 13.7±0.2°, and 13.9±0.2°.

5. The compound 1 crystalline form A hydrate according to claim 1, further characterized by an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 8.7±0.2°, 9.7±0.2°, and 13.9±0.2°, respectively.

6. The compound 1 crystalline form A hydrate according to claim 1, having a differential scanning calorimetry thermogram (DSC) that includes an endothermic peak at approximately 78.0°C.

7. The compound 1 crystalline form A hydrate according to claim 1, having a differential scanning calorimetry thermogram (DSC) that includes a melting transition at approximately 279 to approximately 281°C.

8. The compound 1 crystalline form A hydrate according to claim 1, having substantially the differential scanning calorimetry thermogram (DSC) shown in Figure 3.

9. The compound 1 crystalline form A hydrate according to claim 1, wherein the thermogravimetric analysis (TGA) is substantially as shown in Figure 4.

10. The compound 1 crystalline form A hydrate according to claim 1, further characterized by the IR spectrum substantially shown in Figure 6.

11. 1426 ± 2 cm －１ , 1547±2cm －１ , and 1629±2cm －１ The compound 1 crystalline form A hydrate according to claim 1, further characterized by an IR spectrum having an absorption peak in each of the following regions.

12. The compound 1 crystalline form A hydrate according to claim 1, further characterized by the Raman spectrum substantially shown in Figure 7.

13. 1407 ± 2 cm －１ , 1443±2cm －１ , 1540±2cm －１ , 1578±2cm －１ , and 1628±2cm －１ The compound 1 crystalline form A hydrate according to claim 1, further characterized by a Raman spectrum having a Raman shift for each of the following.

14. 1407 ± 2 cm －１ , 1540 ± 2 cm －１ , and 1578 ± 2 cm －１ The compound 1 crystalline form A hydrate according to claim 1, further characterized by a Raman spectrum having a Raman shift at each of them.

15. The compound 1 crystalline form A hydrate according to claim 1, further characterized by substantially the dynamic vapor adsorption profile shown in Figure 5.

16. The solution in DMSO-d6 is essentially as shown in Figure 8. １ A hydrate of compound 1 in crystalline form A according to claim 1, having a 1H NMR spectral profile.

17. A solution in DMSO-d6 containing one or more peaks at approximately 3.58 ppm, 4.05 ppm, 4.38 ppm, 4.65 ppm, 4.91 ppm, 7.07 ppm, 7.22 ppm, 7.29 ppm, 7.43 ppm, 7.48 ppm, 7.60 ppm, 7.68 ppm, 7.74 ppm, 7.90 ppm, 8.09 ppm, 8.20 ppm, 8.25 ppm, 10.19 ppm, 11.73 ppm, and 11.84 ppm. １ A hydrate of compound 1 in crystalline form A according to claim 1, having a 1H NMR spectrum.

18. A hydrate of compound 1 crystalline form A according to claim 1, having a water content of approximately 2.4 wt% by Karl Fischer titration.

19. A hydrate of compound 1 in crystalline form A according to claim 1, which is a non-stoichiometric hydrate.

20. a) comprising the hydrate of compound 1 crystalline form A described in claim 1, or b) A composition in which the crystalline form A hydrate of compound 1 described in claim 1 is dissolved.

21. The composition according to claim 20, comprising a pharmaceutically acceptable carrier or diluent.

22. The composition according to claim 21, which substantially does not contain crystalline form C anhydrous.

23. a) comprising at least about 50% by weight of compound 1 crystalline form A hydrate, or b) the dissolved crystalline form A hydrate constitutes at least about 50% by weight of the composition, according to claim 21.

24. a) comprising at least about 5% by weight of compound 1 crystalline form A hydrate, or b) the dissolved crystalline form A hydrate constitutes at least about 5% by weight of the composition, according to claim 21.

25. a) comprising at least about 1% by weight of compound 1 crystalline form A hydrate, or b) the dissolved crystalline form A hydrate is at least about 1% by weight of the composition, according to claim 21.

26. Mix methanol and water (v / v) in a ratio of approximately 95:5 to form a slurry with compound 1, This includes stirring the slurry at approximately 40°C for approximately two days. The slurry contains compound 1 crystalline form A hydrate. A method for preparing compound 1 crystalline form A hydrate.

27. A method for producing compound 1 crystalline form A hydrate according to claim 26, further comprising separating the crystalline form A hydrate from a slurry and drying the separated crystalline form A hydrate.

28. Compound 1 Crystalline Form B DMF Solvate.

29. The compound 1 crystal form B DMF solvate according to claim 28, having substantially the X-ray powder diffraction pattern shown in Figure 9.

30. The compound 1 crystalline form B DMF solvate according to claim 28, further characterized by an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) 4.5±0.2°, 7.3±0.2°, 7.7±0.2°, 9.2±0.2°, and 10.3±0.2°, respectively.

31. The compound 1 crystalline form B DMF solvate according to claim 28, further characterized by an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) 4.5±0.2°, 7.3±0.2°, and 10.3±0.2°, respectively.

32. The compound 1 crystalline form B DMF solvate according to claim 28, having a differential scanning calorimetry thermogram (DSC) that includes an endothermic peak at approximately 147.0°C.

33. The compound 1 crystalline form B DMF solvate according to claim 28, having substantially the differential scanning calorimetry thermogram (DSC) shown in Figure 10.

34. The compound 1 crystalline form B DMF solvate according to claim 28, wherein the thermogravimetric analysis (TGA) is substantially as shown in Figure 11.

35. The solution in DMSO-d6 is essentially as shown in Figure 12. １ The compound 1 crystalline form B DMF solvate according to claim 28, having an H NMR spectral profile.

36. A solution in DMSO-d6 containing one or more peaks at approximately 3.58 ppm, 4.05 ppm, 4.38 ppm, 4.65 ppm, 4.91 ppm, 7.07 ppm, 7.22 ppm, 7.29 ppm, 7.43 ppm, 7.48 ppm, 7.60 ppm, 7.68 ppm, 7.74 ppm, 7.90 ppm, 7.95 ppm, 8.10 ppm, 8.20 ppm, 8.25 ppm, 10.19 ppm, 11.73 ppm, and 11.84 ppm. １ The compound 1 crystalline form B DMF solvate according to claim 28, having an H NMR spectrum.

37. The compound 1 crystalline form B DMF solvate according to claim 28, which is a DMF solvate.

38. a) comprising the crystalline form B DMF solvate described in claim 28, or b) A composition in which the crystalline form B DMF solvate described in claim 28 is dissolved.

39. The composition according to claim 38, comprising at least one pharmaceutically acceptable carrier or diluent.

40. a) comprising at least about 50% by weight of compound 1 crystalline form B DMF solvate, or b) the dissolved crystalline form B DMF solvate constitutes at least about 50% by weight of the composition, according to claim 39.

41. a) comprising at least about 5% by weight of compound 1 crystalline form B DMF solvate, or b) the dissolved crystalline form B DMF solvate constitutes at least about 5% by weight of the composition, according to claim 39.

42. a) comprising at least about 1% by weight of compound 1 crystalline form B DMF solvate, or b) the dissolved crystalline form B DMF solvate is at least about 1% by weight of the composition.

43. Mixing DMF and compound 1 crystalline form A hydrate to form a solution, This includes stirring the solution to obtain a slurry. The slurry contains crystalline form B DMF solvate. A method for preparing compound 1, crystalline form B, DMF solvate.

44. A method for producing compound 1 crystalline form B DMF solvate according to claim 43, further comprising separating the crystalline form B DMF solvate from a slurry and drying the separated crystalline form B DMF solvate.

45. Compound 1 Crystalline Form C Anhydrous.

46. The compound 1 crystalline form C anhydrous according to claim 45, having substantially the X-ray powder diffraction pattern shown in Figure 13.

47. The compound 1 crystalline form C anhydrous according to claim 45, further characterized by an X-ray powder diffraction pattern containing peaks at diffraction angles (2θ) of 9.8±0.2°, 11.7±0.2°, 12.0±0.2°, 13.4±0.2°, and 15.2±0.2°.

48. The compound 1 crystalline form C anhydrous according to claim 45, further characterized by an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) 9.8±0.2°, 11.7±0.2°, and 15.2±0.2°, respectively.

49. The compound 1 crystalline form C anhydrous according to claim 41, having substantially the differential scanning calorimetry thermogram (DSC) shown in Figure 14.

50. The compound 1 crystalline form C anhydrous according to claim 45, having a differential scanning calorimetry thermogram (DSC) that includes an endothermic peak at approximately 100.55°C.

51. The compound 1 crystalline form C anhydrous according to claim 45, wherein the thermogravimetric analysis (TGA) is substantially as shown in Figure 15.

52. The compound 1 crystalline form C anhydrous according to claim 45, further characterized by the IR spectrum substantially shown in Figure 17.

53. 1402 ± 2 cm －１ , 1421±2cm －１ , 1539±2cm －１ , and 1616±2cm －１ The compound 1 crystalline form C anhydrous according to claim 45, further characterized by an IR spectrum having an absorption peak in each of the following regions.

54. The compound 1 crystalline form C anhydrous according to claim 45, further characterized by the Raman spectrum substantially represented in Figure 18.

55. 1399 ± 2 cm －１ , 1584±2cm －１ , and 1623±2cm －１ The compound 1 crystalline form C anhydrous according to claim 45, further characterized by a Raman spectrum having a Raman shift for each of the elements.

56. The compound 1 crystalline form C anhydrous according to claim 45, further characterized by the dynamic vapor adsorption profile substantially shown in Figure 16.

57. The solution in DMSO-d6 is essentially as shown in Figure 19. １ The compound 1 crystalline form C anhydrous according to claim 45, having an H NMR spectral profile.

58. A solution in DMSO-d6 containing one or more peaks at approximately 3.58 ppm, 4.05 ppm, 4.38 ppm, 4.65 ppm, 4.91 ppm, 7.07 ppm, 7.22 ppm, 7.29 ppm, 7.43 ppm, 7.49 ppm, 7.60 ppm, 7.68 ppm, 7.74 ppm, 7.90 ppm, 8.09 ppm, 8.20 ppm, 8.25 ppm, 10.19 ppm, 11.73 ppm, and 11.84 ppm. １ The compound 1 crystalline form C anhydrous according to claim 45, having an H NMR spectrum.

59. a) comprising the compound 1 crystalline form C anhydride described in claim 45, or b) A composition in which the crystalline form C anhydride described in claim 45 is dissolved.

60. The composition according to claim 59, comprising at least one pharmaceutically acceptable carrier or diluent.

61. The composition according to claim 59, which substantially does not contain crystalline form A hydrate.

62. a) comprising at least about 50% by weight of compound 1 crystalline form C anhydride, or b) the dissolved crystalline form C anhydride constitutes at least about 50% by weight of the composition, according to claim 61.

63. a) comprising at least about 5% by weight of compound 1 crystalline form C anhydride, or b) the dissolved crystalline form C anhydride constitutes at least about 5% by weight of the composition, according to claim 61.

64. a) The composition comprising at least about 1% by weight of Compound 1 crystalline form C anhydride, or b) The composition comprising at least about 1% by weight of dissolved crystalline form C anhydride.

65. Mixing acetonitrile and crystalline form A hydrate to form a slurry, This includes stirring the solution at approximately 40°C for about one week. The slurry contains crystalline form C anhydrous, A method for preparing compound 1, crystalline form C, anhydrous.

66. A method for producing compound 1 crystalline form C anhydrous according to claim 65, further comprising separating crystalline form C anhydrous from a slurry and drying the separated crystalline form C anhydrous.

67. Mixing anhydrous ethanol and crystalline form A hydrate to form a slurry, This includes stirring the slurry at approximately 40°C for approximately two days. The slurry contains crystalline form C anhydrous, A method for preparing compound 1, crystalline form C, anhydrous.

68. A method for producing compound 1 crystalline form C anhydrous according to claim 67, further comprising separating crystalline form C anhydrous from a slurry and drying the separated crystalline form C anhydrous.

69. Mixing anhydrous ethanol and crystalline form A hydrate to form a slurry, This includes stirring the slurry at approximately 50°C for approximately 1 hour. The slurry contains crystalline form C anhydrous, A method for preparing compound 1, crystalline form C, anhydrous.

70. A method for producing compound 1 crystalline form C anhydrous according to claim 67, further comprising separating crystalline form C anhydrous from a slurry and drying the separated crystalline form C anhydrous.

71. Compound 1 Crystalline Form E DMSO Solvate.

72. The compound 1 crystalline form E DMSO solvate according to claim 71, having substantially the X-ray powder diffraction pattern shown in Figure 20.

73. The compound 1 crystalline form E DMSO solvate according to claim 71, further characterized by an X-ray powder diffraction pattern containing peaks at diffraction angles (2θ) 6.0±0.2°, 6.5±0.2°, 8.6±0.2°, 9.1±0.2°, and 11.9±0.2°.

74. The compound 1 crystalline form E DMSO solvate according to claim 71, further characterized by an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) 6.0±0.2°, 6.5±0.2°, and 8.6±0.2°, respectively.

75. The solution in DMSO-d6 is essentially as shown in Figure 21. １ The compound 1 crystalline form E DMSO solvate according to claim 71, having an H NMR spectral profile.

76. A solution in DMSO-d6 containing one or more peaks at approximately 2.53 ppm, 3.58 ppm, 4.05 ppm, 4.38 ppm, 4.65 ppm, 4.91 ppm, 7.07 ppm, 7.22 ppm, 7.29 ppm, 7.43 ppm, 7.48 ppm, 7.60 ppm, 7.68 ppm, 7.74 ppm, 7.90 ppm, 8.09 ppm, 8.20 ppm, 8.25 ppm, 10.19 ppm, 11.73 ppm, and 11.84 ppm. １ The compound 1 crystalline form E DMSO solvate according to claim 71, having an H NMR spectrum.

77. The crystalline form E of compound 1 according to claim 71, which is a DMSO solvate.

78. Mixing DMSO and crystalline form A hydrate to form a solution, Next, water is added dropwise to form a slurry, This includes stirring the slurry for about one day. The slurry contains crystalline form E DMSO solvate. A method for preparing compound 1, crystalline form E, and DMSO solvate.

79. A method for producing compound 1 crystalline form E DMSO solvate according to claim 78, further comprising separating the crystalline form E DMSO solvate from a slurry and drying the separated crystalline form E DMSO solvate.

80. a) comprising the crystalline form E DMSO solvate described in claim 71, or b) A composition in which the crystalline form E DMSO solvate described in claim 71 is dissolved.

81. The composition according to claim 80, comprising at least one pharmaceutically acceptable carrier or diluent.

82. a) comprising at least about 50% by weight of compound 1 crystalline form E DMSO solvate, or b) the dissolved crystalline form E DMSO solvate constitutes at least about 50% by weight of the composition, according to claim 81.

83. a) comprising at least about 5% by weight of compound 1 crystalline form E DMSO solvate, or b) the dissolved crystalline form E DMSO solvate constitutes at least about 5% by weight of the composition, according to claim 81.

84. a) comprising at least about 1% by weight of compound 1 crystalline form E DMSO solvate, or b) the dissolved crystalline form E DMSO solvate is at least about 1% by weight of the composition.

85. Compound 1 Crystalline Form F DMA Solvate.

86. The compound 1 crystalline form F DMA solvate according to claim 85, having substantially the X-ray powder diffraction pattern shown in Figure 22.

87. The compound 1 crystalline form F DMA solvate according to claim 85, further characterized by an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) 7.8±0.2°, 8.1±0.2°, 9.1±0.2°, 9.5±0.2°, and 9.9±0.2°, respectively.

88. The compound 1 crystalline form F DMA solvate according to claim 85, further characterized by an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) 8.1±0.2°, 9.1±0.2°, and 9.9±0.2°, respectively.

89. The solution in DMSO-d6 is essentially as shown in Figure 23. １ The compound 1 crystalline form F DMA solvate according to claim 85, having an H NMR spectral profile.

90. A solution in DMSO-d6 containing one or more peaks at approximately 1.95 ppm, 2.78 ppm, 2.94 ppm, 3.58 ppm, 4.05 ppm, 4.38 ppm, 4.65 ppm, 4.91 ppm, 7.07 ppm, 7.22 ppm, 7.29 ppm, 7.43 ppm, 7.48 ppm, 7.60 ppm, 7.68 ppm, 7.74 ppm, 7.90 ppm, 8.09 ppm, 8.20 ppm, 8.25 ppm, 10.19 ppm, 11.73 ppm, and 11.84 ppm. １ A compound 1 crystalline form F DMA solvate according to claim 85, having an H NMR spectrum.

91. The compound 1 crystalline form F DMA solvate according to claim 85, which is a DMA solvate.

92. The compound 1 crystalline form F DMA solvate according to claim 91, which is a mono-DMA solvate.

93. a) comprising the crystalline form F DMA solvate described in claim 85, or b) A composition in which the crystalline form F DMA solvate described in claim 85 is dissolved.

94. The composition according to claim 93, comprising at least one pharmaceutically acceptable carrier or diluent.

95. a) comprising at least about 50% by weight of a compound 1 form F DMA solvate, or b) the dissolved crystalline form F DMA solvate constitutes at least about 50% by weight of the composition, according to claim 94.

96. a) comprising at least about 5% by weight of a compound 1 form F DMA solvate, or b) the dissolved crystalline form F DMA solvate constitutes at least about 5% by weight of the composition, according to claim 94.

97. a) comprising at least about 1% by weight of a compound 1 form F DMA solvate, or b) the dissolved crystalline form F DMA solvate is at least about 1% by weight of the composition.

98. DMA:H (approximately 70:30) ２ A slurry is formed by mixing O with a mixture of compound 1 crystalline form A hydrate and compound 1 crystalline form C anhydrous, This includes stirring the slurry for about one week. The slurry contains crystalline form FDMA solvate. A method for preparing compound 1, crystalline form F, and DMA solvate.

99. A method for producing compound 1 crystalline form F DMA solvate according to claim 98, further comprising separating the crystalline form F DMA solvate from a slurry and drying the separated crystalline form F DMA solvate.

100. Compound 1, crystalline form A, nonstoichiometric hydrate, characterized in that it is converted to the crystalline form C anhydrous compound described in claim 45 in anhydrous ethanol at a temperature of 50°C for about 1 hour.

101. Compound 1, crystalline form A hydrate, characterized in that it is converted to the crystalline form C anhydrous described in claim 45 in anhydrous ethanol at a temperature of about 40°C for about 2 days.

102. Compound 1, crystalline form A, hydrate, substantially free of compound 1, crystalline form C, anhydrous.

103. Compound 1, crystalline form C, anhydrous, substantially free of compound 1, crystalline form A, hydrate.

104. A method for treating cancer in a mammal that requires it, comprising the step of administering an effective amount of any one of the crystalline forms A to F of compound 1 according to any one of claims 1, 28, 45, 71, and 85 to the mammal.

105. The method according to claim 104, wherein the cancer is a solid tumor cancer.

106. Solid tumor cancers include fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endosarcoma, lymphangiosarcoma, lymphangiosarcoma, synoviomas, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, stomach cancer, oral cancer, nasal cancer, throat cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystitis The method according to claim 105, wherein the cancer is battadenoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, cholangiocarcinoma, choriocarcinoma, seminomas, fetal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, small cell lung cancer, bladder cancer, lung cancer, epithelial carcinoma, glioma, glioblastoma multiforme, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pineal glandoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, skin cancer, melanoma, neuroblastoma, retinoblastoma, or hepatocellular carcinoma.

107. The method according to claim 104, wherein the cancer is a blood cancer.

108. The method according to claim 107, wherein the blood cancer is leukemia, lymphoma, or myeloma.

109. The method according to claim 108, wherein the blood cancer is leukemia, and the leukemia is acute leukemia or chronic leukemia.

110. The method according to claim 108, wherein the blood cancer is leukemia, and the leukemia is lymphoblastic leukemia, myeloid leukemia, lymphocytic leukemia, myeloid leukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute monoblastic leukemia, acute erythroleukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute nonlymphoblastic leukemia, acute anaplastic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, or hairy cell leukemia.

111. The method according to claim 108, wherein the blood cancer is lymphoma, and the lymphoma is Hodgkin's disease, non-Hodgkin lymphoma, Waldenström macroglobulinemia, heavy chain disease, or polycythemia vera.

112. The method according to claim 108, wherein the blood cancer is myeloma, and the myeloma is solitary plasmacytoma, extramedullary plasmacytoma, or multiple myeloma.

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